Pathogenic breaches: how viruses compromise blood-tissue barriers

Apoorva; Sunit K Singh

doi:10.1080/21688370.2025.2549020

. 2025 Aug 30;14(1):2549020. doi: 10.1080/21688370.2025.2549020

Pathogenic breaches: how viruses compromise blood-tissue barriers

Apoorva ^a, Sunit K Singh ^a,^b,^c,^✉

PMCID: PMC12959211 PMID: 40884531

ABSTRACT

Blood-tissue barriers (BTBs) are highly specialized, selectively permeable surfaces that separate the circulatory system from delicate tissues and organs. Critical examples include the blood-brain barrier (BBB), blood-retinal barrier (BRB), blood-testis barrier (BTB), and other organ-specific barriers, including the alveolar-capillary interface in the lungs and the glomerular filtration barrier in the kidneys. These barriers regulate the bidirectional transport of nutrients, gases, and waste while restricting pathogens, toxins, and immune cells to maintain physiological balance. Nevertheless, viruses have evolved multiple strategies to circumvent or compromise these barriers, facilitating viral entry, evading immune surveillance, and establishing infection within protected compartments. Neurotropic viruses, including the West Nile virus and Japanese encephalitis virus, impair the blood-brain barrier by disrupting tight junction proteins and cytokine storms. In contrast, respiratory viruses such as influenza and SARS-CoV-2 affect the lung barrier, resulting in alveolar injury and systemic inflammation. Other viruses, such as the Zika virus, affect the BTB and placental barriers, presenting significant risks to fetal development and reproductive health. Such breaches facilitate viral spread, exacerbate tissue damage, and complicate therapeutic interventions. This review provides a comprehensive overview of blood-tissue barrier architecture, function, and mechanisms of viral disruption, highlighting their dual role in protection and susceptibility during viral infections. By elucidating interactions between viruses and blood-tissue barriers, this work highlights emerging research directions to mitigate viral pathogenesis and enhance treatment efficacy for barrier-associated diseases.

KEYWORDS: Cytokines, endothelial cells, junction proteins, viral receptors, viruses

1. Introduction

The blood-tissue barrier is a specialized interface that functions as a selective gatekeeper by separating the circulatory system from a broad range of tissues.^1,2 It is an essential component of the body’s defense mechanism. Endothelial or epithelial cells joined by tight junctions inhibit the passive diffusion of hazardous chemicals, pathogens, and immune cells in these dynamic barriers.^3–5 Basement membranes and auxiliary cells, such as astrocytes, brain endothelial cells, pericytes, and placental trophoblasts, allow blood-tissue barriers to establish as a multi-layered defense system.^1,2,6 Functionally, blood-tissue barriers employ a combination of tight junction proteins (claudins, occludins), selective transporters (GLUT1, and metabolic enzymes that detoxify toxic chemicals.^7,8 Efflux pumps like P-glycoprotein aggressively expel xenobiotics. Notable examples of blood-tissue barriers include the blood-brain barrier (BBB), blood-testis barrier (BTB), blood-retinal barrier (BRB), blood-air barrier (BAB), and blood-CSF barrier (BCB).^1,2,8–10

Among the blood-tissue barriers, BBB (Figure 1) has always been the subject of extensive study.^11–18 However, each of these blood-tissue barriers has unique structural and functional characteristics.^1,2,9,10,19 The BBB features tightly sealed endothelial cells reinforced by astrocytic end feet and pericytes. This arrangement minimizes paracellular leakage and employs specialized transporters, such as GLUT1, to shuttle glucose into the brain.^7,8 In contrast, the BTB, formed by tight junctions between Sertoli cells rather than endothelial cells, isolates developing sperm from the immune system, creating an immunologically privileged niche for spermatogenesis.²⁰ Similarly, the placental barrier combines fetal endothelial cells with a maternal syncytiotrophoblast layer to facilitate nutrient and antibody transfer (e.g., via FcRn receptors).^21,22 Interestingly, variations exist even within the endothelial-derived blood-tissue barriers: the BRB incorporates both endothelial and epithelial layers to prevent fluid leakage into the retina, which is critical for visual function.^9,10

Beyond their protective role, blood-tissue barriers maintain tissue homeostasis. They precisely regulate the exchange of substances between the bloodstream and tissue microenvironments, ensuring that different tissues maintain their susceptible interior habitats.¹ To maintain proper organ function, these blood-tissue barriers regulate the flow of nutrients like glucose and oxygen while preventing the entry of harmful toxins and pathogens.^1,2 For instance, the BBB regulates ion balance and neurotransmitter levels to maintain a stable environment for neuronal functions.^23–25 The blood-lung barrier facilitates the exchange of gases in the lungs but blocks the entry of inhaled contaminants/pathogens. Similarly, the blood-tissue barrier in the liver is involved in drug metabolism and detoxification process, whereas the blood-tissue barrier in the kidney filters blood while simultaneously reabsorbing essential elements.¹ In addition, blood-tissue barriers provide immune protection by enabling restricted/controlled immune cell infiltration while preventing pathogens from entering sensitive tissues.^1,2,23–25

Despite this, viruses have evolved mechanisms to breach these barriers, leading to viral infections (Table 1).^{32,33,46,47,49,56–63} Viruses such as Human immunodeficiency virus type 1 (HIV), Dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV) have the potential to compromise the integrity of the BBB, which can lead to neuroinvasion and subsequent neuroinflammation.^{32,33,56,59,62–66} HIV and ZIKV exploit cell-surface receptors, such as CCR5, to hijack macrophages as “Trojan horses” to infiltrate the central nervous system (CNS), causing HIV-associated dementia or congenital Zika syndrome.³⁸ Cytomegalovirus (CMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV) can compromise the BRB, leading to vision impairment.^42,67 Hepatitis B and C viruses (HBV and HCV) target the liver’s sinusoidal endothelial cells, facilitating direct access to hepatocytes.^68,69 Similarly, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reported to disrupt the blood-air barrier in the lungs.⁷⁰ SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors on alveolar epithelial cells, causing junctional protein degradation, vascular permeability, and acute respiratory distress.⁷¹ ZIKV and mumps virus (MuV) exploit BTB for their persistence, to evade immune surveillance, causing orchitis (inflammation of the testes) and potential infertility.^38,48 Viruses utilize receptor-mediated mechanisms, immune cell infiltration, or direct barrier disruption to establish a productive/persistent infection. This review summarizes the current literature on the molecular and cellular mechanisms exploited by pathogenic viruses to cross a variety of blood-tissue barriers.

Table 1.

Viruses affecting blood-tissue barrier integrity.

S. No.	Virus	Type of blood tissue barrier	Mechanism	Dysfunction	References
1.	Severe Acute Respiratory Syndrome Coronavirus	Blood-air barrier	Infects alveolar epithelial and endothelial cells, leading to inflammation and increased permeability of the blood-air barrier	Acute respiratory distress syndrome (ARDS) is characterized by fluid leakage into the alveoli, impaired gas exchange, and hypoxemia	²⁶
2.	Severe Acute Respiratory Syndrome Coronavirus-2	Blood-air barrier	Infects alveolar epithelial and endothelial cells, leading to inflammation and increased permeability of the blood-air barrier	Acute respiratory distress syndrome (ARDS) is characterized by fluid leakage into the alveoli, impaired gas exchange, and hypoxemia	²⁶
3.	Influenza Virus	Blood-air barrier	Endocytosis of IAV virions by the alveolar epithelium	ARDS, increased alveolar permeability	²⁷
4.	West Nile Virus	Blood-brain barrier	WNV invades BBB via infected immune cells or disruption of tight junctions	Increased BBB permeability, CNS invasion, and encephalitis	²⁸
5.	Japanese Encephalitis Virus	Blood-brain barrier	Infects endothelial cells and astrocytes	Increased BBB permeability, CNS invasion, and encephalitis	^29–31
6.	Human Immunodeficiency Virus	Blood-brain barrier	Infects endothelial cells, and pericytes, and disrupts tight junctions	HIV-associated neurocognitive disorders (HAND)	^32–35
7.	Ebola Virus	Blood-brain barrier	Infects endothelial cells and macrophages	Viral encephalitis and neurological complications	³⁶
8.	Herpes Simplex Virus	Blood-brain barrier	Apoptosis of BBB cells, activation of inflammatory pathways, and disruption of tight junctions	Encephalitis, neural infection	^34,37
9.	Zika Virus	Blood-brain barrier	Crosses BBB via transcytosis, disrupts tight junction proteins, infects endothelial cells, astrocytes, and pericytes	Microcephaly, neurological damage	^30,38–40
10.	Zika Virus	Blood-placental barrier	Disrupts the syncytial monolayer, and crosses via transcytosis	Microcephaly	³⁸
11.	Epstein-Barr Virus	Blood-brain barrier	Infecting cells within BBB, trigger neuroinflammation	Associated with multiple sclerosis, and CNS lymphomas	³⁴
12.	Measles Virus	Blood-brain barrier	Transmigration of infected monocytes, junction protein receptor	Subacute sclerosing panencephalitis (SSPE)	⁴¹
13.	Human Herpesvirus 6	Blood-brain barrier	Direct neuronal damage, release of cytokines, and altered permeability	Encephalitis, particularly in immunocompromised patients	³⁴
14.	Cytomegalovirus	Blood-retinal barrier	Infects retinal endothelial cells and retinal pigment epithelial cells	Retinitis	^42–45
15.	Varicella-Zoster Virus	Blood-retinal barrier	Viral spread via infected T cells and inflammation-induced damage	Acute retinal necrosis, vision impairment	⁴⁶
16.	Hepatitis B Virus	Blood-testis barrier	Infects Sertoli cells, sperm cells, spermatogonial cells, and primary spermatocytes	Potential impact on reproductive health; presence in semen	⁴⁷
17.	Mumps Virus	Blood-testis barrier	Triggers TLR2-mediated TNF-α production	Orchitis, potential infertility	⁴⁸
18.	Dengue Virus	Vascular endothelial barrier	Infects endothelial cells and pericytes disrupt junction proteins	Increased vascular permeability, leading to DHF and DSS	^49–55

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2. Endothelial cells: gatekeepers of blood-tissue barriers

The core component of the blood-tissue barrier is the endothelial layer, forming a continuous lining of blood vessels (Figure 2a).⁵ The structure of the different blood-tissue barriers varies across different tissues (Table 2). For instance, the BBB is characterized by highly developed TJs and a close association with astrocytic end feet.⁸ In contrast, the blood-lung barrier exhibits fenestrated capillaries to facilitate gas exchange while maintaining a certain degree of barrier selectivity.

Table 2.

Structure and function of different blood tissue barriers.

Type of blood-tissue barrier	Structure/Anatomy	Tight junctions	Location	Function
Blood-brain barrier	Consists of endothelial cells, astrocyte end-feet, pericytes, and tight junctions	Tight junctions between endothelial cells of brain capillaries	Between blood and brain’s extracellular fluid	Prevents entry of neurotoxic compounds and pathogens; facilitates nutrient and waste exchange
Blood-CSF barrier	Composed of tight junctions in choroid plexus epithelial cells	Tight junctions in choroid plexus epithelial cells	Choroid plexus (CP) of the brain ventricles	Regulates exchange between blood and CSF; maintains CSF composition; protects the brain from blood borne pathogens
Blood-retinal barrier	Comprised of inner (consists of retinal endothelial cells) and outer (consists of retinal epithelial cells) blood retinal barriers	Inner BRB: Tight junctions between retinal endothelial cells; Outer BRB: Tight junctions between retinal pigment epithelium (RPE)	Between the blood and inner retinal microvasculature	Maintains retinal environment for proper vision; protects retinal cells from blood toxins; supports nutrient and oxygen transport
Blood-testis barrier	Formed by Sertoli cells in the seminiferous tubules	Tight junctions between sertoli cells	Between blood vessels and the seminiferous tubules in the testes	Protects developing germ cells from harmful substances and immune cells; regulates the microenvironment for spermatogenesis
Blood-air barrier	Composed of alveolar epithelial cells, capillary endothelial cells and a shared basement membrane	–	Between alveolar air and blood in lungs	Prevents pathogen entry; facilitates gaseous exchange (oxygen and carbon dioxide between air and blood)
Blood-placental barrier	Composed of fetal endothelial cells and layers of trophoblast cells	–	Between maternal and fetal blood in placenta	Protects fetus from harmful substances; regulates nutrient and gaseous exchange

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Endothelial cells line the interior of blood vessels.^4,5 The vasculature comprises around 6 × 10^{1 1} endothelial cells, encompassing a surface area of 4,000–7,000 m² in adults.⁵ They serve as selective gatekeepers crucial in limiting the passage of molecules. In most blood-tissue barriers, endothelial cells have specialized properties that reduce permeability.^4,5 The blood-tissue barrier endothelial cells are characterized by tight junction proteins (TJPs), lack/presence of fenestrations, and reduced pinocytosis. For instance, endothelial cells found in the brain are often densely packed in continuous endothelia to reduce the amount of passive diffusion.⁸ Conversely, fenestrated endothelia, such as those found in the kidneys, have pores that improve permeability.¹ These cells also have transporters and receptors for regulating substance exchange.^4,7 Their cytoplasmic surface is coated with glycocalyx, a carbohydrate-rich coating that repels pathogens and large harmful substances.^2,72 They are critical entry routes for viral infections, particularly in the lower respiratory tract, where alveolar epithelial and lung microvascular endothelial cells enable gaseous exchange.⁵ Viral attachment to endothelial cells varies in specificity and is influenced by interactions between viral glycoproteins and cell receptors (Table 3).⁵ The endothelial glycocalyx contains glycan and protein receptors that affect viral binding; however, the mere presence of these receptors does not guarantee infection.^53,72 To facilitate viral entry, coronaviruses, including SARS-CoV-2, bind to ACE2 receptor via the spike (S) protein.⁸⁵ Henipavirus G is reported to specifically target vascular endothelial tyrosine kinase EphrinB2, whereas hantaviruses were found to interact with β3-integrin, gC1qR, or protocadherin-1.^86,87 Additionally, flaviviruses and filoviruses are shown to utilize scavenger receptors such as TIM-1 or TAM family receptors to facilitate extensive cellular attachment.⁵ Evidences suggest that the attachment of viruses to endothelial cells is a crucial determinant in the spread of infection and the severity of disease (Figure 2c). Although endothelium infection may not be necessary for viral replication, studies have shown that endothelium infection may worsen illness, warranting additional studies.⁵

Table 3.

Viral entry receptors on different components of the blood tissue barrier.

BTB component	Virus	Entry receptors	References
Endothelial cells	Severe acute respiratory syndrome coronavirus 2	ACE-2	⁵
	Nipah virus	EphrinB2(B3)
	Hendra virus	EphrinB2(B3)
	New world hantavirus	β3-integrin, Protocadherin-1
	Influenza A virus subtype H5N1	α-2–3-linked N-acetyl-sialic acid
	Influenza A	α-2–3-linked N-acetyl-sialic acid
	Influenza A virus subtype H7N1	α-2–3-linked N-acetyl-sialic acid
Tight junctions	Adenovirus	CAR (CAR^EX7, CAR^EX8)	^73,74
	Coxsackievirus B	CAR, OCLN	^73,74
	Human hepatitis C virus	CLDN-1, CLDN-6, CLDN-9, OCLN	^75–78
	Dengue virus	CLDN-1	⁷⁴
	Rotavirus	JAM-A, ZO-1, OCLN, CLDN-1	⁷⁹
	Reovirus	JAM-A
	Feline calicivirus	JAM-A
Epithelial cells	Herpes simplex virus	Nectin 1, HVEM	⁸⁰
	Varicella-zoster virus	Man6-P/IGFII-R, Nectin 1
	Human cytomegalovirus	HSPG
	Epstein-Barr virus	CR2 (CD21), Poly lg-receptor
	Human immunodeficiency virus	CCR5
	Respiratory syncytial virus	ICAM1, VLDLR
	Sendai virus	Sialyoligosaccharide
	Black Creek Canal virus	Integrin-β₃
	Influenza virus	Sialyoligosaccharide
	Human papilloma virus	HSPG
	Adeno-associated virus	HSPG
	Jamestown Canyon virus	Sialyoligosaccharide
	Adenovirus	CAR
	Coxsackievirus	CAR
	Rhinovirus major group	ICAM1
	Rhinovirus minor group	LDLR family
	Echovirus	Integrin-α₂β₁
	Human parechovirus	Integrin-α₂β₁
Astrocytes	Herpes simplex virus-1	HSPGs, αvβ3	⁸¹
	Severe acute respiratory syndrome coronavirus 2	ACE2	⁸²
		NRP1	⁸³
		CD147	⁸¹
		DPP4	⁸¹
		TMPRSS2	⁸²
	Zika virus	AXL	⁴⁰
	Echovirus 1	α2β1	⁸⁴
	Human immunodeficiency virus	DC-SIGN	⁸¹
	Middle East respiratory syndrome coronavirus	CD147, DPP4	⁸¹
Pericytes	Severe acute respiratory syndrome coronavirus 2	ACE-2	³⁹
Pericytes	Human immunodeficiency virus	CD4, CXCR4, CXCR5	^35,39

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3. Tight junctions: flexible regulators of blood-tissue barriers

Tight junctions (TJs) ensure barrier integrity by joining adjacent endothelial cells.^3,73 They block the passage of pathogens through the paracellular route. However, many blood-tissue barriers are not static structures. Instead, TJs undergo continuous remodeling. They undergo continuous disassembly, reassembly, and stabilization. These processes are under tight physiological control, ensuring proper function and permeability.^74,88 The key proteins include claudins (CLDNs), occludins (OCLN), and zonula occludens (ZO) proteins.^73,75,89 However, many viruses exploit TJs as receptors to cross blood-tissue barriers, facilitating their infection and spread (Table 3) (Figure 2d).^73,74,88 Adenoviruses (Adv) and Coxsackieviruses utilize coxsackievirus and adenovirus receptor (CAR), to trigger the disassembly of TJs, as a primary receptor. Adenovirus attachment to CAR initiates integrin-mediated entry, resulting in TJ disruption to reach to the basolateral integrins such as integrins αvβ3 and αvβ5, α5β1, as well as αvβ and α3β1.⁷³ Coxsackieviruses facilitate CAR trafficking at TJs by binding to DAF (decay-accelerating factor) and inducing Rac-dependent cytoskeletal rearrangements.⁷³ WNV degrades TJ proteins JAM-A, ZO-1, OCLN, and CLDN-1.²⁸ Similarly, during DENV infection impairs TJs’ integrity on endothelial cells and exhibit changes in expression of adherens junctions, ZO-1 and the actin cytoskeleton.⁵⁴ The retroviruses, such as: HIV and human T-cell lymphotropic virus (HTLV), have been reported to dysregulate the expression of TJPs to accomplish hematogenous spread.⁷³ Further, HCV entry depends on CLDN1 and OCLN, which are reported to function in conjunction with CD81.^76,77,90 HSV-1 and HSV-2 infections are the most prevalent opportunistic infections among AIDS patients.³⁷ Recent research has shown that HIV proteins Tat and gp120 can disrupt TJs, allowing HSV-1 and HSV-2 to spread paracellularly.³⁷ Rotaviruses can utilize TJPs for their entry.⁷⁹ It has been demonstrated that ZO-1, OCLN, and JAM-A are crucial for viral internalization.⁷⁹ The C-terminal region of JAM-A appears to be crucial for rotavirus entry into non-polarized fetal kidney cells.⁷⁹ JAM-A is also a functional receptor for feline calicivirus.⁷³ Many viruses have adapted to employ TJPs as receptors for cellular invasion because this circumvents their barrier function of epithelial and endothelial cells.^{73–75,88,91}

Numerous studies have shown that cytokines, lysophospholipids, and their receptors govern GTPase signaling in brain endothelial cells to influence endothelial cell junction integrity.^92–94 In multiple sclerosis, heightened expression of sphingosine-1-phosphate receptor 2 (S1PR2), particularly in females, enhances BBB permeability through the activation of Rho/ROCK pathways, which destabilize endothelial junctions.⁹⁵ Conversely, signaling via type I IFN, IFN-λ, and the TAM receptor (Mertk) has shown protective effects against viral entry into the brain.^92–94 Type I IFN enhances and maintains BBB integrity. The induction of cytokines through pattern recognition pathways directly influences BBB permeability and tight junction formation by modulating the activation of small GTPases Rac1 and RhoA, subsequently regulating the transendothelial trafficking of WNV.⁹⁴ IFN-λ, through noncanonical signaling via IFNLR1, is also reported to enhance the integrity of the BBB and limit WNV neuroinvasion.⁹³ The synergistic effect of TAM receptor (Mertk) and IFN-β is shown to enhance the integrity of cell junctions and inhibit viral passage through brain microvascular endothelial cells in West Nile and La Crosse encephalitis virus infection.⁹² These molecules protect against the neuroinvasion, by enhancing endothelial cell junction integrity and decreasing BBB permeability. This functional balance is regulated at the molecular level by the competing activities of small GTPases. Disruptive signals lead to RhoA-mediated permeability, whereas protective signals facilitate Rac1-mediated barrier stabilization.^92–94

4. Pericytes: essential vascular regulators

Pericytes are very important for keeping the blood-tissue barrier intact. They are found in the basement membrane and wrap the endothelial cells that line the capillaries throughout the body. They control blood flow and vascular permeability, adjust vascular width through contractile properties, and support the intactness of TJs by secreting signaling molecules, for instance, angiopoietin-1.³⁹ Furthermore, pericytes interact with astrocytes and endothelial cells in brain to strengthen the overall function of the BBB. Numerous viruses, such as ZIKV, HIV, JEV, and HCMV, are reported to infect pericytes (Figure 2c).^{35,39,52,96–98} Infection of pericytes has predominantly been observed within the pericytes of the BBB, indicating a potentially shared function of pericytes in the neuropathogenesis associated with these viruses.³⁹ The modulation of inflammatory responses is a frequent consequence of pericyte infection, which implies that pericytes should not be neglected when examining the broader role of immune dysfunction in viral pathogenesis. Viral gene products are often secreted into the extracellular space, where these secreted proteins may facilitate widespread adverse effects without productive viral infection.⁵⁶ For instance, the HIV-1 transactivator of transcription (Tat) is released from infected cells and has been associated with the progression of HAND.⁹⁶ Recombinant soluble Tat enhanced cell migration in-vitro when exposed to primary human brain vascular pericytes and the pericyte-like C3H/10T1/2 cell line.⁹⁶ Moreover, there is a notable reduction in pericyte coverage within brain microvessels, as evidenced by biopsies from individuals suffering from HIV encephalitis and in transgenic (Tg26) mice that express HIV-Tat.^39,96 This observation implies that the Tat-induced dysfunction and/or loss of pericytes may play a significant role in the advancement of HAND.³⁹ Severe DENV infection poses a substantial risk of mortality and is characterized by microvascular hyperpermeability across multiple organs and the onset of circulatory shock.⁵⁵ The NS1, a glycoprotein released into the circulatory system as a hexamer, alters the endothelium glycocalyx and induces permeability in primary human endothelial cell monolayers in-vitro.^39,52 Furthermore, we and others have reported the in-vitro effects of DENV-2 NS1 on endothelial cells and primary human pericytes.^{52,57,66,99,100} Recombinant soluble NS1 treatment has also disrupted pericyte-endothelial cell connections in 3D cocultures and enhanced barrier permeability without altering pericyte migration or survival.³⁹ Disruption of pericyte-endothelial cell contact-independent paracrine signaling was a moderating factor in these effects.^39,52 HCMV and SARS-CoV-2 are also reported to affect pericyte-related signaling molecules, although their effects are less well understood than those of DENV or HIV.³⁹ The recent findings show that pericytes have a critical but poorly understood role in virus-associated vascular leakage.

5. Basement membrane: a key component of blood-tissue barrier architecture

The vascular basement membrane provides support to endothelial cells and pericytes.⁸ It is a thin extracellular matrix layer composed mainly of laminin and collagen. It facilitates structural stability, anchors cells, and is essential for the maturation of barriers.^6,101 In addition to mechanical function, the basement membrane regulates cell signaling and blood-tissue barrier maintenance.^1,8,24 It helps with molecular filtration and barrier integrity due to its selective permeability, which lets small molecules flow but restricts larger entities. This dynamic structure is crucial for maintaining vascular stability.^1,8,24 It ensures that the endothelium functions properly. Viruses may compromise the basement membranes by inducing MMP activity, triggering barrier disruption.^99,102–104 For instance, SARS-CoV-2 traverses the BBB through a transcellular mechanism, facilitating its entry into the brain parenchyma, despite the presence of intact tight junctions. SARS-CoV-2 infection is documented to enhance BBB permeability in K18-hACE2 mice and hamsters, primarily due to disruption of the basement membrane rather than alterations in TJs. The virus directly infects brain microvascular endothelial cells (BMECs), leading to the upregulation of MMP9 and the degradation of collagen IV, thereby compromising the BBB structure.¹⁰⁵ Furthermore, the alveolar basement membranes – both epithelial and vascular – were found to be disrupted in COVID-19 patients.¹⁰⁶ Similarly, HIV-1 envelope glycoprotein 120 (gp120) is reported to activate MMP and degrade vascular basement membrane.¹⁰⁷

6. Glial cells: architectural support to the blood-brain barrier

Glial cells, primarily astrocytes (star-shaped glial cells), are crucial for maintaining the integrity of the BBB.²⁴ Astrocyte endfeet covers more than 99% of the BBB’s endothelium, working closely with endothelial cells to strengthen tight connections and maintain barrier function.^81,108 They produce signaling factors that enhance endothelial tight junctions, control the balance of ions and water important for neuronal health, and offer metabolic support by delivering energy substrates and eliminating waste products.^81,109,110 Astrocytes and endothelial cells work together in the neurovascular unit to keep the BBB intact and functional.⁸ Astrocytes are among the initial cell types a virus encounters when it crosses the BBB.^81,108,111 The intricate architecture of astrocytes shows that their cell expansions can branch out into hundreds of smaller processes, allowing them a substantially greater membrane contact with the extracellular area.^81,112,113 Also, astrocytes are known to express a plethora of viral entry receptors, which play a key role in targeting certain viruses to different cell types (Figure 2b).^81,108 Like other cell types, astrocytes allow viruses to enter the body by binding viral surface proteins to plasma membrane receptors. A single virus can infect a host by simultaneously exploiting multiple receptors for entry.⁸¹ Numerous potential viral entry receptors have been confirmed in astrocytes (Table 3).⁸¹ During JEV infection, astrocytes are reported to release VEGF, IL-6, and MMPs, which activate ubiquitin proteasome-mediated degradation of ZO-1 and CLDN-5, weakening the endothelium barrier. Further, high IFN-γ levels in HIV infection decrease astrocytic heme oxygenase-1 via immunoproteasome degradation, leading to increased neurotoxic glutamate levels and cognitive impairment.¹¹⁴ The CXCL1 released through astrocytes, recruits’ neutrophils into the brain via increased BBB permeability in HSV-1 encephalitis.¹¹⁵ The ZIKV E protein similarly activates astrocytes, leading to a pro-inflammatory state that compromises endothelial tight junctions.¹¹⁶ Conversely, astrocytes play a crucial role in host defense. In WNV infection, astrocyte-specific type I IFN signaling is crucial for maintaining BBB integrity, especially in the cerebellum.¹¹⁷ In flaviviral encephalitis, RIPK3 mediated signaling in astrocytes results in the production of serpins, which inhibit immune cell infiltration and maintain the barrier.¹¹⁸ In addition, astrocytes may function as a sustained viral reservoir. Astrocytes in HIV infection can harbor the virus and promote its egress from the brain to peripheral organs, even during antiretroviral therapy, while maintaining the structural integrity of the blood-brain barrier.¹¹⁹ Despite the enormous importance of astrocytes in neurotropic viral infections, only a few studies have thoroughly investigated how viruses exploit cellular processes in this cell type.

7. Tissue-specific adaptations

The fundamental components of blood-tissue barriers are conserved across various tissues; however, they also demonstrate tissue-specific adaptations to fulfill distinct functional requirements. BBB employs astrocytes, pericytes, and specialized transporters (e.g., LAT1) to sustain the brain while simultaneously blocking neurotoxins.^7,8,120 Similar to the BBB, BRB is made up of pigmented epithelial cells. BRB has additional layers of cells and tight junctions.⁹ The BTB is established by TJs between Sertoli cells in the seminiferous tubules.²⁰ The blood-placental barrier (BPB) utilizes a unique structure called syncytiotrophoblast (STB) for the exchange of nutrients and waste products between the mother and fetus.^21,22 The BAB comprises alveolar epithelium and endothelium, which enable gas exchange and inhibit fluid leakage via tight junctions.^2,121

8. Viral routes and pathways to disrupt barrier function

8.1. Viral infiltration tactics

Viruses employ numerous strategies to infiltrate host cells and breach barriers based on their structure (enveloped or non-enveloped) and the characteristics of the host cells.^122,123 The two main routes are receptor-mediated endocytosis and direct penetration. However, macropinocytosis and signaling pathway activation are also reported. Viruses utilize direct membrane fusion (e.g., herpes simplex virus) or receptor-mediated endocytosis, such as ACE2 for SARS-CoV-2, often facilitated by co-receptors (CXCR4/CCR5 for HIV). HSV directly fuses with the host plasma membrane, releasing its genetic material into the cytoplasm.¹²² Recent research has shown that many host cell components play a crucial role in viral internalization, even when direct association with the virus particle is absent. This has led to the concept of “entry factors.”¹²² For instance, the tight junction proteins CLDN-1 and OCLN appear to have an indirect role in HCV entry.⁷⁶

Viruses are shown to cross blood-tissue barriers via the transcellular pathway (through cells), paracellular pathway (between cells), and the “Trojan horse” mechanism. Viruses can traverse through host cells by transcellular pathways via either adsorptive transcytosis (based on charge interactions) or receptor-ligand mediated transcytosis (needs specific binding).¹²⁴ In addition, several viruses take advantage of clathrin- or caveolin-mediated endocytosis, with endosomal pH or calcium levels initiating uncoating for their entry (e.g., influenza virus).¹²³ VEEV and WEEV are reported to enter the CNS by utilizing caveolin-mediated transcytosis via hematogenous dissemination across an intact BBB.¹²⁵ Additionally, cellular polarity influences viral entry; specialized cells such as Peyer’s patch M cells facilitate transcytosis, whereas apical or basolateral entry influences the outcome of infection.⁸⁰ The trojan horse mechanism involves migrating infected immune cells like monocytes (e.g., HIV) across barriers.¹²⁶ Caprine arthritis encephalitis virus and Visna virus are reported to invade BBB by the “Trojan horse” mechanism.³⁴ ZIKV is reported to increase vesicular trafficking to cross BBB in brain microvascular endothelial cells.³⁸ Viruses may also exploit the paracellular pathway by disrupting tight junctions (e.g. HIV-1).⁷³ Some viruses compromise the barrier’s integrity by destroying tight junctions in a bystander manner or by receptor modulation (CLDN-5 in the case of Enterovirus A71).⁷³ For instance, the NS1 protein of DENV, JEV, and WNV upregulates the cathepsin L and endoglycosidase heparinase expression in endothelial cells. This leads to the degradation of glycocalyx-like layer (EGL) components, resulting in high BBB permeability.^53,60,127 The non-hematogenous routes of viral entry into the CNS are retrograde axonal transport and trans-synaptic trafficking.¹¹⁴ Additionally, pathogen-specific strategies such as using poly-immunoglobulin receptors by Epstein-Barr virus and exploiting hematogenous dissemination and axonal transport by arboviruses are also reported.^80,128–131

8.2. Structural sabotage of tight and adherens junction

Viruses can breach and impair the integrity of the barriers that separate blood and surrounding tissues.^{32,33,49,52,56–59,61–65,75,91,132,133} JEV is reported to alter host apoptotic protein expression, weakening BBB tight junctions.¹³⁴ The Hepatitis E virus (HEV), in a similar manner, modulates the expression of ZO-1, CLDN5, and OCLN at endothelial TJs, which in turn weakens the BBB.¹³⁵ ZIKV can penetrate the BTB by targeting testis Sertoli cells, spermatogonia, and primordial spermatocytes.³⁸ HIV-Tat and gp120 proteins down-regulate adhesion proteins such as OCLN, CLDN, and ZO-1, enabling HIV-1 to penetrate the BBB.^32,33,56,64 Viral-induced blood-tissue barrier disruption mechanisms include direct cellular damage, inflammation and cytokine storm, disruption of tight junctions, and induction of cellular stress. The TJs and AJs are crucial components of the blood-tissue barriers. The epithelial and endothelial barriers have almost similar characteristics.⁸⁸ Viruses are reported to directly interact with the TJs of the brain, airway, and intestinal epithelial cells.^54,73,74 Some components of the viral TJs and AJs work as viral entry factors or attachment receptors.^73,75 JAM-1 is reported to be a receptor for reovirus and feline calicivirus.⁷³ The measles virus exploits Nectin-4, an AJP, as an epithelial cell receptor.⁴¹ OCLN is reported to facilitate entry of Coxsackievirus B3.⁷³ CLDN-1‘s location in TJs is crucial for HCV particle entry because mutations in the first extracellular loop prevent CLDN-1 from establishing cell-cell interactions. CLDN-1, CLDN-6, and CLDN-9 interact with CD81 to facilitate viral entry and HCV internalization.^75,76 OCLN is another TJ protein linked to HCV entry; overexpression of this protein causes a dramatic increase in HCV absorption even in cells that aren’t vulnerable to infection.⁷³ The exact mechanism by which OCLN contributes to HCV entry is unknown. Recently, it was discovered that the dengue virus protein prM/M can also bind CLDN-1, and the knockdown of prM/M in Huh 7.5 cells prevents viral entry.¹³⁶ However, the mechanisms underlying the exploitation of tight junctions as entry receptors remain poorly understood. Despite being utilized as entry receptors, several viruses are reported to disrupt these junction proteins (Figure 3). HCV infection alters tight junction integrity by promoting the expression of vascular endothelial growth factor.¹³⁷ Hantavirus infection of renal epithelial and endothelial cells reduced transepithelial electrical resistance and tight junction protein ZO-1.¹³⁸ DENV infection induces macrophage migration inhibitory factor and causes tight junction protein ZO-1 re-distribution, increasing vascular permeability.^139,140 HIV Tat protein is reported to activate the RhoA signaling pathway to disrupt the TJs and induce nuclear localization of ZO-1.⁶⁴ Several studies have reported that EV-A71 capsid protein VP reduces the expression of CLDN-5. EV-A71 capsid protein VP also increases the expression of the virus receptor vimentin in endothelial cells, resulting in increased vascular permeability to facilitate viral entry.^73,74 HIV-1 alters tight junction proteins via monocyte chemoattractant protein-1 (CCL2). By altering the actin cytoskeleton and tight junction protein distribution in brain endothelium, CCL2 is reported to disrupt BBB. Although cytoskeleton integrity is altered in several viral infections, its involvement in viral-induced BBB disruption is poorly understood.¹⁴¹

Figure 3. — Viruses disrupt the expression or function of tight junction proteins to compromise the barrier integrity. ZO-1, OCLN, JAM-1, and CLDNs are important components of TJ that contribute to intracellular signaling, preserve cell polarity, and create a selective paracellular barrier. Viruses alter or downregulate TJPs to enter, propagate, or evade the immune system.

Abbreviations: AAV, Adeno-Associated Virus; AdV, Adenovirus; CLDN, Claudin; CMV, Cytomegalovirus; DENV, Dengue Virus; EBOV, Ebola Virus; EV-A71, Enterovirus A71; HCV, Hepatitis C Virus; HIV, Human Immunodeficiency Virus; HSV, Herpes Simplex Virus; IAV, Influenza A Virus; JAM-1, Junctional Adhesion Molecule 1; JEV, Japanese encephalitis virus; OCLN, Occludin; PCV2, Porcine circovirus 2; PRRSV, Porcine Reproductive and Respiratory Syndrome Virus; RABV, Rabies Virus; RSV, Respiratory Syncytial Virus; RuV, Rubella Virus; RV, Rhinovirus; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; TJPs, Tight junction proteins; VZV, Varicella-Zoster Virus; WNV, West Nile virus; ZIKV, Zika virus; ZO-1, Zona occludin-1.

8.3. Cytokines and barrier disruptions

Cytokines and chemokines are released during viral infection as an inflammatory response.^142–144 Although inflammation is necessary for viral clearance, a “cytokine storm,” characterized by sustained inflammation, can compromise the barrier integrity.^145,146 Viruses often trigger these responses either directly or through positive feedback loops. Viruses infect immune cells and alter their function, causing them to release many cytokines.¹⁴⁴ SARS-CoV-2 and DENV have been shown to infect endothelial cells, resulting in increased permeability and leakage.^{142,143,147,148} Viruses recognized by PRRS on immune cells trigger the release of cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ. The initial cytokine release can enhance immune responses, establishing a feedback loop that exacerbates inflammation and tissue damage.^142,143 Cytokines released during viral infections are also reported to disrupt tight junctions between endothelial cells, increasing the barrier permeability.^66,142,147 DENV and EBOV are reported to disrupt endothelial barriers by triggering cytokine storms, contributing to hemorrhagic fevers and multi-organ failure.^36,147 SARS-CoV-2 is reported to cause excessive activation of macrophages and T cells, triggering cytokine storm, which disrupts the blood-air barrier in the lungs.^146,149 High levels of cytokine production in case of influenza virus infection are reported to reduce ZO-1, leading to increased vascular permeability.¹⁵⁰ The influenza virus is reported to cause severe pneumonia and ARDS by inducing cytokine release and damaging the blood-air barrier.¹⁵¹ Immune cell infiltration has been shown to disrupt barrier integrity. The inflammatory response generated during viral infection is reported to recruit immune cells, such as neutrophils and macrophages, to the infection site. These further damage the barrier integrity by releasing proteases and reactive oxygen species.^{66,142,144,147,151} Altogether, the dysregulated expression of cytokines and disruption of blood-tissue barriers during viral infections are critical aspects of viral pathogenesis.

8.4. Direct cellular damage leading to disruption of barrier integrity

Viruses induce direct cellular damage via cytopathic effects (CPE), apoptosis, and necrosis, which play a significant role in viral pathogenesis. CPE arises when viruses exploit host cell machinery for replication, disrupting normal cellular functions, resulting in protein synthesis overload, and ultimately causing cell lysis or syncytia formation, thereby compromising the blood-tissue barrier integrity.¹⁵² Certain viruses form inclusion bodies that disrupt organelle function. HIV is reported to compromise brain microvascular endothelial cells (BMECs), impairing the BBB, whereas influenza virus affects lung epithelial cells, hindering gas exchange.¹⁵³ Apoptosis serves as a critical mechanism utilized by numerous viruses to compromise physiological barriers, thereby facilitating viral spread. Viruses are reported to induce apoptosis through the activation of caspases, mitochondrial damage, or endoplasmic reticulum stress, resulting in regulated cell death.^134,154 Necrosis, in contrast, occurs as a result of uncontrolled cell death stemming from lysis or a disruption in cellular homeostasis.¹⁵⁵ ZIKV is reported to induce apoptosis in neural progenitor cells, thereby affecting brain development.³⁸ IAV induces apoptosis through intrinsic and extrinsic pathways by decreasing anti-apoptotic proteins (Mcl-1, Bcl-xL) and increasing Bax/Bak levels. This process is frequently initiated by the viral protein PB1-F2, which interacts with mitochondrial channels (VDAC1, ANT3), resulting in mitochondrial permeabilization and the release of cytochrome c. IAV suppresses anti-apoptotic regulators such as API5 and FLIP, which enhances death receptor signaling (FasL, TRAIL) and leads to epithelial barrier damage.¹⁵⁶ JEV enhances BBB permeability through the upregulation of Bax, BID, Fas, and FasL, alongside the induction of IL-6 production in pericytes, which leads to endothelial damage and barrier disruption.¹³⁴ DENV induces the release of cytochrome c, activates caspases, and facilitates NF-κB translocation, thereby compromising the integrity of neuronal and endothelial cells. Flavivirus-infected neurons are reported to undergo apoptosis and activate resident microglia, leading to an inflammatory response. The production of inflammatory cytokines (e.g., TNF-α, IL-1β, INF-γ, and IL-4), chemokines (e.g., CCL2, CCL5, CXCL9, CXCL10), inflammatory enzymes (COX-2), and MMPs results in the degradation of the endothelial barrier and the release of inflammatory factors, which recruit CD4+ and CD8+ T lymphocytes into the CNS parenchyma. The infiltration of CD4+/CD8+ T lymphocytes contributes to increased inflammation and ultimately results in central nervous system damage.¹⁵⁷ These mechanisms collectively demonstrate how viruses undermine cellular integrity and influence disease severity.

8.5. miRNA-mediated dysregulations leading to barrier disruptions

MicroRNAs are short, non-coding RNAs that regulate gene expression post-transcriptionally.¹⁵⁸ miRNAs bind to the target mRNAs, leading to their degradation or translational repression.¹⁵⁸ Although miRNAs are essential for cellular homeostasis, viral infections often dysregulate the expression of miRNAs, to invade and disseminate across epithelial and endothelial tissue barriers.^66,158–163 This occurs through a variety of processes. miRNAs can target and downregulate the expression of tight and adherens junction proteins essential for maintaining barrier integrity.¹⁶⁴ HIV-1 Tat C has been reported to modulate the expression of miRNA-101 to suppress VE-cadherin in human brain microvascular endothelial cells.⁵⁶ miR-182 is reported to target a tight junction protein CLDN1 during HCV infection and facilitate virus internalization.¹⁶⁵ ZIKV-NS1 targets adherens junction proteins in human brain microvascular endothelial cells via the hsa-miR-29b-3p/DNMT3b/MMP-9 pathway, compromising barrier function.⁶⁵ During HCMV infection, miR-34a promotes apoptosis by targeting anti-apoptotic genes such as BCL2, whereas Epstein-Barr virus (EBV) downregulates miR-15a and miR-16–1, extending infected cell life and allowing persistent barrier dysfunction.¹⁶⁶ miR-148a and miR-145 are upregulated in Zika-infected endothelial cells, promoting apoptosis and disrupting the BBB.¹⁶⁷ This allows the virus to cross the barrier and infect neural progenitor cells, leading to microcephaly and other developmental abnormalities.^38,167 miRNAs have the potential to interfere with cytoskeletal dynamics, which in turn can change the shape and adherence of barrier cells. miR-200c, for example, impairs epithelial-mesenchymal transition (EMT), reducing epithelial cell adhesion during viral infections.^168–170 DENV NS1 is reported to activate RhoA-mediated cytoskeleton contractility and alter the endothelial barrier integrity via miRNA-9-5p in a bystander fashion.⁶⁶ Furthermore, miRNAs can potentially exacerbate inflammation, resulting in the disruption of barrier tissue. miR-155, miR-221, and miR-126 are reported to regulate EC permeability and inflammation during DENV infection.¹⁷¹ Similarly, miR-155 inhibits SOCS1, a negative JAK/STAT pathway regulator, resulting in uncontrolled activation of NF-κB and STAT3 signaling. This increases the cytokine storm and causes endothelial dysfunction.¹⁷² Additionally, viruses can affect host defenses by either encoding their miRNAs or exploiting the miRNAs of the host.¹⁷³ However, current research focuses on host-derived miRNA-mediated barrier disruption, with little evidence on the involvement of viral-encoded miRNAs in barrier disruption. DENV infection causes severe complications such as dengue hemorrhagic fever and dengue shock syndrome, characterized by vascular leakage.¹⁷⁴ Aloia et al. (2015) reported the involvement of miR-126, miR-155, miR-221, and miR-222 in DENV-induced endothelial cell inflammation and maintenance of vascular integrity.¹⁷⁵ Additionally, miR-146a dysregulation exacerbates inflammation, further compromising the blood-retinal barrier.^176,177 Downregulation of miR-221 and miR-222 is reported to regulate HIV Tat-induced expression of ICAM-1, a cell adhesion molecule, facilitating immune cell trafficking across the BBB and contributing to neuroinflammation.^178,179 The miRNA-mediated alterations may contribute to viral pathogenesis by weakening barrier defenses and enabling systemic dissemination.

9. Viruses traversing across blood-brain barrier

9.1. Flaviviruses

Flaviviruses are positive sense, single-stranded RNA viruses. Certain flaviviruses, such as WNV, JEV, ZIKV, HCV, and DENV, exhibit enigmatic neurotropic and neurovirulent characteristics, allowing them to invade the CNS and lead to neurological conditions, for example, encephalitis and meningitis.^{34,39,108,130} The NS1 of flaviviruses, particularly DENV, ZIKV, and WNV is reported to bind to endothelial cells in a tissue-specific manner, inducing vascular leakage by disrupting the endothelial glycocalyx layer. This disruption is mediated by clathrin- and dynamin-dependent endocytosis of NS1 and is dependent on a conserved N207 glycosylation site.¹⁸⁰ Additionally, protective monoclonal antibodies targeting flavivirus NS1 have been demonstrated to inhibit flavivirus NS1–triggered endothelial dysfunction.¹⁸¹

ZIKV may compromise the blood – tissue barriers by affecting endothelial integrity. Since the virus targets the neural tissue of the developing fetus, the sensitivity of brain endothelial cells to ZIKV is of utmost significance.¹⁸² ZIKV can interfere with brain development and induce tissue damage by traversing the fetal BBB and influencing angiogenesis. Shao et al. (2016) demonstrated that the ZIKV-infected fetus had aberrant brain blood vessel density and a leaky BBB.¹⁸³ ZIKV infection may result in embryonic endothelial cell necrosis, which might account for fetal brain injury.¹⁸² However, the effect of ZIKV on endothelial cell permeability in-vivo differs from the results obtained using an in-vitro model.¹⁸² ZIKV may replicate and produce infectious viruses, however, it does not influence brain endothelial cell monolayer permeability in-vitro. The in-vitro model confines infection to endothelial cells, functioning as a closed system. Conversely, in-vivo models encompass the interactions among ZIKV-infected endothelium cells, adjacent tissue, and leukocytes.¹⁸² Moreover, different ZIKV subtypes cause different effects on TJ protein expression. ZIKV-PR and ZIKV-U downregulate ZO-1, OCLN, and CLDN-5, increasing BBB permeability and promoting viral invasion into the brain parenchyma. ZIKV-H upregulates ZO-1 and maintains BBB integrity. In addition, in-vitro studies have demonstrated that ZIKV infection in human brain vascular pericytes increases endothelial barrier permeability. This suggests that ZIKV may also utilize pericyte infection for CNS invasion.³⁹

JEV-induced Japanese encephalitis causes significant neuroinflammation and BBB degradation.^30,34 JEV disrupts BBB by reducing CLDN-5 and ZO-1. Additionally, JEV infection alters inflammatory cytokine/chemokine expression. JEV is reported to infect BMECs and astrocytes. The BBB permeability caused by JEV requires BMEC-astrocyte interaction, which promotes inflammatory cytokine release.³¹ Tohidpour et al. (2017) found that microglia produce inflammatory species such as IL-1β, IL-6, MCP-1, TNF-α, and iNOS, which weaken the endothelium barrier.¹⁸⁴ Activated microglia and astrocytes in JEV-infected mice are reported to release cytokines such as CCL5, CXCL10, CCL2, TNF-α, IL-6, and IFN-γ in the CNS.³⁴ Li et al. (2015) have also reported JEV RNA in mice after 2 dpi and BBB degradation after 4 dpi.²⁹ However, according to Chang et al. 2015, JEV disrupts the BBB via a bystander effect rather than directly infecting BBB endothelial cells.³¹ JEV is also reported to infect rat brain microvascular pericytes and induce the production of proinflammatory cytokines, thereby increasing the permeability of primary rat endothelial cell monolayers in in-vitro studies.³⁹ Additionally, the induction of proinflammatory cytokines, namely IL-6 and RANTES in JEV-infected mice brain perivascular cells in-vivo is also reported.³⁹ JEV-infected pericytes are reported to activate the TLR7/MyD88 signaling, resulting in IL-6 and CCL5 production. IL-6 secreted by JEV-infected pericytes induces the expression of Ubr1, a ubiquitin-protein ligase in brain endothelial cells. Ubr1 disrupts the barrier integrity by facilitating proteasomal degradation of ZO-1.¹¹⁴

Among the flaviviruses, DENV is regarded as the primary cause of neurological manifestations. DENV1, DENV2, DENV3, and DENV4 enters into tissues by exploiting the secreted NS1, which disrupts endothelial barriers.^{57,60,127,185} DENV NS1 also disrupts endothelial glycocalyx on human pulmonary microvascular endothelial cells, leading to the degradation of sialic acid and the shedding of heparan sulfate proteoglycans. The effect is mediated by the expression of sialidases and heparanase induced by NS1. NS1 activates cathepsin L, a lysosomal cysteine proteinase, in endothelial cells, which subsequently activates heparanase through enzymatic cleavage. This process results in DENV NS1-induced endothelial glycocalyx disruption and increased endothelial permeability.^127,185 In human endothelial cells exposed to TNF-α and DENV, OCLN levels were found to be significantly reduced. DENV is also reported to significantly reduce the protein level of ZO-1 expression and peripheral localization in epithelial and endothelial cells.⁷⁴ DENV infection in brain cells was first reported by Calderón-Peláez et al. (2019) using DENV serotype 2 in primary cultures of human umbilical vein and rabbit cava vein endothelial cells.⁵⁹ Further, DENV infection induces ROCK reorganization and vimentin activation, resulting in the redistribution of the endoplasmic reticulum to facilitate efficient viral replication and assembly.³⁴ DENV infection also activates endothelial cells, leading to an upregulation of adhesion molecules such as E-selectin, PECAM-1, VCAM-1, and ICAM-1. This process is reported to be characterized by serotype-specific secretion of immune molecules such as CXCL1, CCL2, CCL5, IL-6, and TNF-α.⁵⁹ Similarly, WNV infection induces the intrinsic expression of inflammatory mediators, including type I and type II IFN, IFN-γ, IL-6, IL-1β, and TNF-α, in brain microvascular endothelial cells (BMEC) at the BBB, ultimately compromising the integrity of endothelial cell.³⁴ In-vitro WNV infection in astrocytes is reported to produce matrix metalloproteinases (MMP) which adversely affect the TJ.²⁸ Wang et al. (2008) demonstrated that MMP9-/-mice exhibited resistance to WNV, MMPs are essential for WNV neuroinvasion. WNV infection is shown to increase MMP-1, −3, and − 9 and decrease TIMP-2 in human primary brain cortical astrocytes (HBCA). Further, WNV supernatant, when applied to BMEC, demonstrated a reduction in the expression levels of CLDN and ZO-1. In contrast, opposite results were observed after the treatment of supernatants with MMP inhibitors.³⁴ This indicates that MMP production induced by WNV infection may compromise the BBB, irrespective of infection in endothelial cells. Studies conducted by Wang et al. and Morrey et al. demonstrated an increase in BBB permeability during WNV infection in C57BL/6 mice.^186,187 Despite the lack of cytopathic effects, WNV alters CLDN-1 and enhances E-selectin and VCAM-1 expression levels.³⁰ Furthermore, several pattern recognition receptors (PPRs) identify WNV RNA and trigger innate immune responses. PPR-induced innate cytokines regulate BBB permeability and TJ formation by proportionally activating Rac1 and RhoA. It additionally influences the trans endothelial movement of the virus. Mice with reduced type I IFN signaling or induction [Ifnar (-/-) Irf7(-/-)] have increased BBB permeability and TJ dysregulation post-WNV infection. WNV NY strain infection in mice (C57BL/6) is reported to increase E-selectin, ICAM-1, and VCAM-1 expression levels in the brain. In addition, knockout of ICAM-1 in mice decreased leukocyte infiltration across BBB, implying a reduction in CNS viral load.³⁴ Conclusively, multiple reports indicate that WNV utilizes a transcellular pathway to enter the CNS without disrupting the BBB (Figure 4). Furthermore, it has been well documented that during WNV encephalitis, T lymphocyte infiltration into the CNS is constrained by BBB, limiting most immune cells to perivascular spaces. This immune sequestration helps prevent CNS damage. The effective clearance of cytopathic neurotropic viruses like WNV requires CD8⁺ T cells to enter the parenchyma. McCandless et al. (2008) reported that the chemokine CXCL12 and its receptor CXCR4 play a key role in restricting T cell parenchymal entry in human and murine WNV-infected brains.¹⁸⁸ CXCR4 inhibition enhanced WNV-specific CD8⁺ T cell migration into the CNS parenchyma, improved viral clearance, and reduced immunopathology. In addition, IL-1R1 mediated signaling is critical for regulating CNS entry of virus-specific lymphocytes. Increased CXCL12 at the BBB binds to the CXCR4 receptor on T cell. This is crucial for the full activation of WNV-specific T cells. WNV-specific T cells reduce CXCR4 levels to limit CXCL12-mediated adhesion. These results show how IL-1β and CXCL12 signaling at the BBB work together to control T cell trafficking during viral infection, balancing neuroprotection with antiviral defense.^188,189

Figure 4. — Schematic representation juxtaposing an intact and healthy BBB versus an impaired BBB, highlighting the mechanisms of viral invasions. (a) certain viruses employ receptor-mediated endocytosis, which involves taking advantage of surface receptors on brain endothelial cells to enter the body. (b) viruses can enter endothelial cells directly by hijacking vesicular transport pathways. (c) tight junctions between endothelial cells are loosened, allowing viruses and viral proteins to pass through intercellular gaps paracellularly. (d) viruses disrupt the expression or function of tight junction proteins, weakening BBB integrity. (e) the protective endothelial glycocalyx layer undergoes enzymatic degradation, exposing endothelial cells and facilitating barrier permeability. (f) infected immune cells, such as monocytes or T cells, transmigrate across the BBB and act as carriers, consequently transporting viral particles into the CNS. (g) astrocytes and microglia are stimulated by viral infections or virokines to release pro-inflammatory cytokines such as IL-6 and TNF-α, which further damage the BBB.

Abbreviations: BBB, Blood-brain barrier; DENV, Dengue Virus; EBOV, Ebola Virus; HCV, Hepatitis C Virus; HIV, Human Immunodeficiency Virus; IAV, Influenza A Virus; JEV, Japanese encephalitis Virus; RABV, Rabies Virus; RV, Rhinovirus; WNV, West Nile virus; ZIKV, Zika virus.

Furthermore, HCV RNA has been identified in brain samples from patients, although the concentrations were significantly lower than those found in liver tissues.¹⁹⁰ Human brain microvascular endothelial cells are reported to express all essential HCV entry receptors – CD81, CLDN1, LDLR, and SR-B1 and facilitate viral entry and replication.^190,191 The interaction between the CD81 receptor and the HCV envelope protein E2 facilitates viral internalization via the TJ proteins OCLN and CLDN1. The viral entrance process relies on certain amino acid sequences in CLDN1 and OCLN, particularly those located at their C-terminal and extracellular loops. Early entrance mechanisms also include other TJ-associated proteins such as CLDN12 and co-receptors like scavenger receptor B1 and epidermal growth factor receptor. The localization of HCV particles at TJs is influenced by actin.^74,190 In addition, the activation of microglia and stimulation of macrophages by HCV infection causes neuroinflammation, which in turn releases neurotoxic substances such as nitric oxide and pro-inflammatory cytokines including TNF-α, IL-1, and IL-6. Neuronal apoptosis and demyelination are aided by lower expression of the neuroprotective TIMP-1 and elevated levels of chemokines LIX, RANTES, and ICAM-1. HCV-infected BMECs cause apoptosis, and BBB damage, allowing viral and cytokine infiltration into the brain parenchyma.¹⁹²

9.2. Retroviruses

HIV-1 infiltrates the CNS shortly after systemic infection. Although there are numerous hypotheses regarding how HIV-1 penetrates the central nervous system, the most prevalent theory is that the virus enters the CNS via the “Trojan Horse mechanism” (Figure 4).³⁴ The virus is recognized for its ability to infect host white blood cells via the CXCR4 and CCR5 receptors. Infiltrating, infected monocytes may serve as the primary carriers of HIV-1 across the BBB.³⁴ HIV infection downregulates TJ expression and increases TJ permeability, allowing the virus to pass through the BBB and epithelial cell tight junction barrier.^{32,33,37,56,98,109} Various subtypes of viral proteins exhibit distinct effects on the expression of tight junctions. Human brain microvascular endothelial cells are susceptible to HIV infection, resulting in a significant reduction in the expression of CLDN-5 and ZO-1.⁷⁴ In addition to viral particles, viral proteins or harmful viral products can control TJ expression. The HIV Tat protein is capable of crossing the BBB and is found in the central nervous system of individuals infected with HIV. Tat disrupts the BBB and changes the integrity of the BBB in HIV infection by downregulating the expression of OCLN, CLDN5, and ZO-1. Downregulation of OCLN by HIV-1 Tat is also reported to cause amyloid β accumulation in the brain, causing serious cell damage.⁷⁴

9.3. Alphaviruses

Encephalitic alphaviruses, such as Western and Venezuelan equine encephalitis viruses, employ a distinct mechanism for CNS entry. These viruses traverse the BBB without compromising tight junction integrity or replicating within the cells of the neurovascular unit.^125,193 Cain et al. (2017) reported that interactions between mononuclear and endothelial cells may contribute to BBB disruption during alphavirus encephalitis infections. VEEV strain TC83 is reported to cross CNS through anterograde axonal migration, without directly influencing BBB function.¹⁹³ Further, encephalitic alphaviruses utilize a transcellular pathway, employing caveola-mediated transcytosis to traverse brain endothelial cells, thus circumventing the paracellular barrier. The hematogenous dissemination of VEEV and WEEV into the CNS occurs through caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, a process hindered by IFN and RhoA GTPase inhibitors. IFN signalling facilitates viral restriction in cells of the neurovascular unit, thereby affecting the permissiveness of brain endothelial cells, pericytes, and astrocytes to viral replication. Salimi et al. (2020) demonstrated initial events in virus internalization and Cav-1 association in brain endothelial cells. Cav-1-deficient mice showed reduced CNS VEEV and WEEV titers in the early stages of infection, while viral loads in peripheral tissues remain unaffected, indicating that alphaviruses utilize Cav-MT for entry into the CNS, while IFN differentially regulates this mechanism at the BBB.¹²⁵

9.4. Rhabdoviruses

Encephalomyelitis caused by Rabies virus (RABV) kills around 55,000 individuals annually. RABV infects peripheral neurons at the wound site before entering the central nervous system via sensory and motor neurons. It was recently discovered that mice infected with a laboratory-attenuated virus had increased BBB permeability. In addition, TJs are critical for RABV-induced inflammatory cytokine permeability. In the transwell model, BBB preservation relies on IFN-λ2 and IFN-λ3, which preserve ZO-1 expression and TJ integrity, reducing neuroinflammation. The IFN-λ2 and IFN-λ3 suppress RABV replication and diminish inflammatory cytokine production in primary astrocytes and microglia, limiting BBB permeability and preventing inflammatory cell infiltration.⁷⁴ In addition to RABV, Chandipura virus (CHPV) is also documented to breach BBB. Retrograde transport of CHPV carried by neurotrophins and viral proteins via axonal microtubules to the neuronal cell body following clathrin-mediated endocytosis is critical for CNS invasion. In mice models, CHPV infection causes a robust inflammatory response characterized by high levels of proinflammatory cytokines such as TNF-α, IL-6, and IL-1β, which compromises BBB integrity. CHPV has also been demonstrated to alter TJPs (OCLN and CLDN) in infected mice brains, allowing immune cell infiltration. However, how CHPV directly infects astrocytes, pericytes, and brain microvascular endothelial cells is not well known.¹⁹⁴

9.5. Coronaviruses

Evidence indicates that SARS-CoV-2 can infect CNS, as it has been identified in cerebrospinal fluid from living patients and in postmortem brain tissue from individuals with COVID-19.¹⁹⁵ Several in-vitro and in-vivo studies including human organoids, iPSC-derived neurons, transwell BBB models have demonstrated that the virus can cross BBB. Yamada et al. (2024) found that SARS-CoV-2 infects iPSC-derived brain microvascular endothelial-like cells (iPSC-BMELCs), reducing transendothelial electrical resistance (TEER), downregulating tight junction proteins (CLDN3, CLDN11), and enhancing proinflammatory genes.¹⁹⁶ Findings also demonstrate that SARS-CoV-2 spike protein degrades endothelial TJ proteins, compromising BBB integrity. Wenzel et al, 2021 demonstrated that Mpro of SARS-CoV-2 induces microvascular brain pathology by cleaving NEMO in brain endothelial cells. This cleavage leads to endothelial cell death, contributing to BBB disruption. SARS-CoV-2 was also found to infect and cross through BMECs in an in-vitro BBB model compromising primary BMECs and astrocytes.¹⁰⁵ Human astrocytes derived from neural stem cells are also vulnerable to SARS-CoV-2 infection via the Neuropilin-1 receptor (NRP1). The blockade of NRP1 using neutralizing antibodies significantly diminishes SARS-CoV-2 infection.¹⁹⁷ However, direct infection of SARS-CoV-2 in endothelial cells remains debatable.¹⁹⁸ Constant et al. (2021) have shown that SARS-CoV-2 poorly replicates in human BBB cells. They observed low viral replication in human in-vitro BBB model, however, suggested that SARS-CoV-2 impairs the BBB through immune-mediated inflammation rather than direct endothelial infection.¹⁹⁹

10. Viruses traversing across blood-placental barrier

10.1. Flaviviruses

Among the flaviviruses, ZIKV can cross the blood-placental barrier, potentially leading to fetal infection and adverse pregnancy outcomes like microcephaly, by potentially infecting the placenta and disrupting the barrier’s integrity (Figure 5a). ZIKV transmigration from mother to fetus may vary by gestational stage. Barrier cells, cytotrophoblasts and syncytiotrophoblasts form primary human trophoblasts (PHTs). ZIKV replication is facilitated by cytotrophoblasts, whereas syncytiotrophoblasts are resistant to ZIKV infection. PHTs produced during late gestation are resistant to ZIKV infection because they produce antiviral IFN-λ1. IFN-λ1 protects trophoblast and non-trophoblast cells through both paracrine and autocrine mechanisms.³⁸ ZIKV infection is also reported to disrupt the blood-placental barrier by degrading ZO-1 and OCLN via proteasomal degradation. It has been observed that when ZIKV infects a woman’s placenta, CLDN4 expression drops significantly.⁷⁴ This finding implies that the virus may exert its effects by influencing the paracellular route.

Figure 5. — Schematic representation of blood-placental and blood-retinal barrier breach during viral infection. (a) ZIKV traverses the blood – placental barrier, resulting in placental inflammation and direct infection of the fetus, leading to fetal infection and adverse pregnancy outcomes like microcephaly. (b) viruses such as ZIKV, DENV, and CMV, as well as viral non-structural proteins, have demonstrated the ability to compromise the integrity of the blood-retinal barrier. Viruses target the retinal endothelial cells and retinal pigment epithelium, causing disruption of tight junction proteins and the induction of inflammatory cytokines. This results in heightened vascular permeability, immune cell infiltration, and the potential for vision impairment or retinal pathology.

Abbreviations: CMV, Cytomegalovirus; DENV, Dengue Virus; NS1, Non-structural protein 1; ZIKV, Zika virus.

10.2. Retroviruses

HIV-1 genomic material has been found in trophoblast and Hofbauer cells, suggesting that it is present in both maternal and fetal placenta components and has the ability to replicate there. Endocytosis or damaged villous surfaces allow the virus to pass the trophoblastic barrier.²⁰⁰ Direct cell-to-cell contact, particularly T-cell contact with the placenta, can promote trophoblast infection, which anti-LFA-1 antibodies can block.²⁰¹ Perinatal HIV-1 transmission generally involves viral variations that circumvent maternal immunity, and placental infections may increase transmission risk.²⁰² The involvement of viral proteins, particularly Nef, in this process has been identified. It is believed that the multifunctional protein Nef contributes to HIV pathogenesis and may even have a role in vertical transmission. It is highly conserved between mother and newborn in transmission and induces pro-inflammatory cytokines, reactive oxygen species, and nitric oxide, which are barrier permeability factors. Nef’s ability to cross the placental barrier was validated by its presence in the placenta, amniotic membrane, fluid, and embryo. Nef-induced permeability, which is most likely caused by inflammation and endothelial instability is demonstrated in mice model.²⁰⁰

11. Viruses traversing across blood-retinal barrier

11.1. Flaviviruses

ZIKV has been reported to infect retinal endothelial cells, retinal pigmented epithelial cells, and retinal BRB in-vitro.^39,203 According to a model put forth by Tracoyia Roach and Donald J. (2017), the following sequence of events occurs: ZIKV infects the endothelial cells and pericytes of the retina in the inner BRB, then travels through the choroid capillaries to infect the retinal pigmented epithelial cells of the outer BRB.²⁰³ The induction of the proinflammatory cytokine RANTES and angiogenic factors observed during ZIKV infection in retinal endothelial cells and retinal pericytes is proposed to contribute to congenital ocular disease, frequently observed in microcephalic infants after ZIKV infection (Figure 5b).³⁹ Furthermore, DENV is also reported to impair BRB by direct viral cytopathy, immune-mediated inflammation, and Müller cell dysfunction (Figure 5b). DENV-infected retinal endothelium, pigment epithelial, and Müller glial cells display decreased F-actin structure and increased permeability, affecting ZO-1, OCLN, and cytoskeletal integrity.²⁰⁴ Endothelial hyperpermeability, MMPs, and TLR4 activation by the viral NS1 protein increases vascular leakage. Further, inflammatory cytokines (TNF-α, IL-6, IL-1β) exacerbate BRB breakdown by reducing TJPs and recruiting monocytes and T-cells. Molecular mimicry and immune complex deposition disturb retinal homeostasis, and anti-NS1 antibodies cross-react with endothelial cells and platelets, causing thrombocytopenia. Müller cells, which regulate retinal fluid, exhibit a weak type I interferon (IFN-β/α) response in cell lines like MIO-M1, but strong antiviral and inflammatory responses in primary isolates, including upregulation of ISGs (RSAD2, ISG15) and immunomodulatory ligands (PD-L1/PD-L2) during DENV infection.²⁰⁵ Müller cell dysfunction, cytokine-driven vascular leakage, and thrombocytopenia cause BRB disruption, which causes macular edema, retinal hemorrhages, and vasculitis.^204,205

11.2. Herpesviruses

Herpesviruses, such as VZV, HSV, and CMV are reported to disrupt BRB and cause acute retinal necrosis (ARN) syndrome (Figure 5b). CMV is the most extensively studied virus associated with BRB disruption. CMV-mediated BRB disruption involves direct viral effects, inflammation, and immune response dysregulation, all of which contribute to retinitis, particularly in immunocompromised individuals.^42,43,67,206 RPE cells and endothelial tight junctions govern molecular exchange between the bloodstream and retinal tissue in the BRB.^9,10 CMV is reported to infect retinal endothelium and RPE cells.⁴³ CMV cytopathic effects cause endothelium and RPE cell deaths, weakening the outer BRB and facilitating viral propagation.⁴³ CMV disrupts TJPs (CLDN-5, OCLN, and ZO-1), affects cytoskeletal integrity, and increases barrier permeability. Further, VEGF production is induced by CMV US28 protein, leading to vascular leakage, whereas IE1/IE2 proteins activate NF-κB signaling, resulting in cytokine release.^207,208 In addition, CMV-infected cells release pro-inflammatory cytokines that weaken tight junctions, worsening BRB permeability.⁶⁷ MMP-2 and MMP-9 upregulation degrades the extracellular matrix, further compromising BRB integrity. CMV-attacking immune cells generate ROS and proteases, damaging the barrier. Additionally, receptor-interacting protein kinase 3 (RIP3) activation is reported to increase inflammation and barrier instability during CMV infections.⁶⁷

11.3. Retroviruses

It has been well documented that retroviruses like HIV-1 disrupt BRB structure and function.²⁰⁹ HIV-1 is reported to employ its gp120 glycoprotein to bind with DC-SIGN receptors on the human retinal pigment epithelium (RPE) cells to compromise the BRB. This interaction triggers NF-κB signaling, subsequently leading to the expression of MMPs, specifically MMP-2 and MMP-9. These MMPs destroy extracellular matrix and TJPs, disrupting barrier integrity. Human RPE cells are important MMP producers, and their overexpression is strongly linked to pathological situations such as choroidal neovascularization in age-related macular degeneration.²¹⁰ Furthermore, exposure to gp120 has been demonstrated to downregulate TJPs such as ZO-1, OCLN, CLDN1, CLDN2, CLDN3, CLDN4, and CLDN5, leading to enhanced epithelial permeability and promoting the translocation of HIV-1.²¹¹ In addition to causing structural disruption, gp120 induces oxidative stress in retinal and glial cells, as indicated by diminished glutathione levels and lower antioxidant enzyme activity. Pro-inflammatory cytokines such as IL-6, IL-8, CCL2, CCL5, and TNF-α increase in response to this oxidative stress, exacerbating BRB breakdown.²¹⁰ Additionally, gp120 increases the expression of astrocyte-elevated gene-1 (AEG-1), which facilitates the activation of the NF-κB and MMP2/9 signaling pathways, thereby perpetuating inflammation and compromising barrier integrity.²¹² Taken together, HIV-1, via gp120, interferes with BRB function by accelerating oxidative stress, inflammatory responses and destroying TJs, which are essential for barrier maintenance.^209–212

12. Viruses traversing across blood-testis barrier

12.1. Paramyxoviruses

The Mumps virus (MuV) is reported to compromise BTB through direct infection and inflammatory responses.^20,48,213 In testicular cells, especially Sertoli cells that maintain the BTB, the MuV impairs TJ proteins (OCLN, CLDN), which are essential for barrier integrity. MuV activates TLR2 signaling, leading to increased proinflammatory cytokine TNF-α and decreased OCLN and ZO-1 levels.⁴⁸ The down-regulation of TJ proteins results in a disruption of the BTB and subsequently halts spermatogenesis within the seminiferous tubules.⁴⁸ Simultaneously, the immune response associated with orchitis activates the release of pro-inflammatory cytokines such as TNF-α and IL-6, which enhance vascular permeability and facilitate the recruitment of immune cells to the testes.^48,213 The inflammation exacerbates the breakdown of the BTB, thereby exposing sperm antigens to the immune system and increasing the risk of autoimmune responses, including the production of anti-sperm antibodies. The disruption of the BTB impairs the microenvironment essential for spermatogenesis, leading to germ cell apoptosis, diminished sperm quality, and, in severe instances, testicular fibrosis or atrophy.⁴⁸

12.2. Retroviruses

Studies suggest that retroviruses like HIV-1 compromise BTB, predominantly via its viral proteins Tat and Nef.^141,214,215 Tat protein enhances endocytosis, tight junction permeability, and transcytosis, facilitating viral invasion. Tat alters actin, microtubule (MT), vimentin, and septin cytoskeletons in Sertoli cells without changing their protein levels. Tat protein influences the spatial distribution and expression of actin-regulatory proteins (Eps8 and Arp3), thereby disrupting the spatiotemporal expression of these proteins at the BTB site, without altering their steady-state protein levels. The timely remodeling of actin filaments at the Sertoli cells basal ectoplasmic specialization/BTB, transitioning between bundled and unbundled/branched arrangement to maintain BTB homeostasis, was found to be impaired, resulting in a transient barrier disruption. Additionally, Tat protein was demonstrated to disrupt MT-associated proteins (detyrosinated, acetylated, and tyrosinated α-tubulin, EB1, KIF15) critical for microtubule dynamics. These changes impede MT dynamics essential for supporting SC BTB function. Furthermore, the Tat protein has been shown to disrupt the vimentin- and septin-based cytoskeletons to compromise the structure and function of BTB.²¹⁴ Similarly, the recombinant Nef (rNef) protein can breach the BTB by disrupting important junctional proteins – OCLN, ZO-1 and delocalizing cadherins – N-cadherin, E-cadherin, which ultimately results in the destabilization of cadherin-based epithelial adhesion system.²¹⁵ Taken together, Tat and Nef viral proteins allow HIV-1 to disrupt BTB integrity and enter the testis.

12.3. Coronaviruses

Evidence indicates that SARS-CoV-2 disrupts BTB through inflammatory, cellular, and molecular pathways. SARS-COV-2 increases pro-inflammatory cytokines – TNF-α, IL-1β, and IL-6. The cytokine-mediated inflammation impairs Sertoli cell function and contributes to oxidative stress, further compromising BTB integrity. Specifically, TNF-α enhances BTB permeability via ERK1/2 signaling and inhibits CLDN-11 production. IL-6 is reported to reduce OCLN. Furthermore, the expression levels of TJPs (ZO-1, JAM-A, N-cadherin) and GJPs (connexin-43) necessary for BTB structure and spermatogenesis were found to be significantly decreased.²¹⁶ SARS-CoV-2 structural proteins (S, E, M, and N) modulate junction protein expression through autophagy. The S protein downregulates ZO-1, N-cadherin, and connexin-43 expression levels, while E and M proteins promote autophagosome formation but limit autophagy flux. ZO-1, CLDN-11, and N-cadherin are downregulated by the N protein. The E protein increases IL-1 and TGF-β levels, whereas all structural proteins activate FasL gene expression. This suggests that autophagy is a key regulatory mechanism in BTB disruption.²¹⁷ Moreover, SARS-CoV-2 binding to ACE2, a receptor present in all testicular cells, may dysregulate the RAS, lowering anti-inflammatory Ang 1–7 and favoring inflammation. In addition, immune cell infiltration and endothelial apoptosis may increase inflammation and oxidative stress. Altogether, SARS-CoV-2 disrupts BTB via cytokine-induced inflammation, apoptosis, ACE2-RAS dysregulation, and autophagy-mediated modulation of junctional proteins.^216–218

12.4. Flaviviruses

Among the flaviviruses, ZIKV has a remarkable affinity for human Sertoli cells, which form BTB and maintain an immune-privileged testes milieu. The immunosuppressive property of SCs – IL-10 production and immune checkpoint expression – allows ZIKV to avoid immune detection and facilitates ZIKV reservoir formation in the testes. Although ZIKV infection in Sertoli cells does not directly impair barrier integrity, ZIKV-infected macrophages secrete pro-inflammatory cytokines (e.g., TNF-α, IL-1β) that disrupt Sertoli cells TJPs causing immune cell infiltration, thereby increasing BTB permeability.²¹⁹ ZIKV infection or ZIKV E protein exposure is also reported to disrupt BTB by rearrangement of the actin cytoskeleton. Reorganization of the F-actin cytoskeleton weakens the interaction between F-actin and ZO-1.²²⁰ Furthermore, ZIKV-infected macrophages are reported to upregulate the expression of MMP9, which disrupts TJPs such as CLDN-1 and OCLN and type IV collagens. The upregulation of MMP-9 is stabilized by NS1-induced K63-linked polyubiquitination, causing BTB disruption and immune cell infiltration.²²¹

13. Viruses traversing across blood-air barrier

13.1. Orthomyxoviruses

Influenza is a viral infection that primarily affects the respiratory system. Influenza A virus (IAV) lung infection compromises the alveolar barrier, which is essential for protecting airspace integrity.²⁷ The barrier consists of closely linked alveolar epithelial and endothelial cells, utilizing junctional proteins including CLDNs, OCLNs, ZO-1, and E-cadherin to regulate fluid and protein permeability. IAV infection causes barrier dysfunction via direct and indirect mechanisms (Figure 6). Viral exposure decreases junctional protein levels through transcriptional suppression, as seen with H1N1‘s inhibition of OCLN, ZO-1, and E-cadherin expression, or through post-translational degradation, evidenced by H5N1-induced Itch-dependent ubiquitination.^27,222 Pharmacological inhibition of upstream regulators such as TAK1 strengthens junctional integrity and increases survival in infected models. IAV indirectly exacerbates edema by promoting proinflammatory signaling, epithelial cell death, and alveolar ion channel dysregulation (e.g., poor fluid clearance). Infection of alveolar type 2 (AT2) epithelial cells can impair surfactant secretion, leading to increased alveolar surface tension and exacerbating edema, a mechanism corroborated by both experimental and theoretical models. Differences in viral factors specific to strains may account for the increased severity observed in pandemic or avian IAV strains, although the exact mechanisms are not yet understood.²⁷ However, the relationship between surfactant loss and barrier permeability, the impact of edema on viral dispersion in alveoli, and the role of strain-specific viral-host interactions in illness outcomes remain unknown. A deeper insight into the IAV-mediated disruption of BAB may aid in IAV-induced lung damage treatments related to barrier repair, and inflammatory management (Figure 6).

Figure 6. — Schematic representation juxtaposing an intact and healthy blood-air barrier versus an impaired blood-air barrier during viral infection. SARS-CoV-2 primarily targets alveolar epithelial and endothelial cells via ACE2 receptors, leading to barrier disruption through cytokine-mediated inflammation, endothelial dysfunction, and tight junction degradation. In contrast, IAV infects epithelial cells of the respiratory tract and disrupts the barrier via direct cytopathic effects, enhanced protease activity, and neutrophil-mediated tissue injury. SARS-CoV-2 targets alveolar epithelial and endothelial cells via ACE2 receptors, causing cytokine-mediated inflammation, endothelial dysfunction, and tight junction breakdown. Viruses such as IAV compromise the respiratory tract barrier by direct cytopathic effects, increased protease activity, and neutrophil-mediated tissue damage.

Abbreviations: IAV, Influenza A Virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

13.2. Coronaviruses

As the main barrier directly regulating gas exchange, the BAB is likely the first tissue barrier to be selectively targeted by SARS-CoV-2. Any insult to this extremely thin part of the alveoli could impair ventilation and lead to hypoxia. SARS-CoV-2 may penetrate the vascular wall by breaching the endothelial barrier (Figure 6).²⁶ An airway-on-a-chip model that replicates respiratory organs was used to evaluate SARS-CoV-2‘s effect on the endothelial barrier. Virus particles from infected epithelial cells reduced CLDN5 expression and impaired vascular endothelial cadherin-mediated adherens junctions, disrupting the barrier.^26,223 Similarly, lung tissue gene and protein analysis of COVID-19 patients indicated lower CLDN5 expression levels. Furthermore, endothelial barrier integrity was successfully restored by either fluvastatin treatment or overexpression of CLDN5. These findings indicate that CLDN5 downregulation is essential for SARS–CoV–2–induced pulmonary endothelial barrier breakdown and suggest CLDN5 upregulation as a possible COVID-19 treatment.²²³ Although there has been no direct evidence of SARS-CoV-2 infection of pericytes, the virus’s entry receptor, ACE2, is abundantly expressed in both mouse olfactory and human cardiac pericytes.³⁹ Research suggests that SARS-CoV-2 spike protein in cardiac pericytes leads to enhanced migration, decreased endothelial support, and elevated proinflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) and proapoptotic factors.²²⁴ The decreased pericyte coverage in the alveolar capillaries of COVID-19 patients provides evidence that pericyte dysfunction may be a contributing factor in the cardiovascular and respiratory symptoms that are associated with COVID-19.²²⁵

13.3. Paramyxoviruses

Respiratory syncytial virus (RSV) is a single-stranded, negative-sense RNA virus classified under the Paramyxoviridae family. RSV infection induces disruption of the airway epithelial barrier, which may facilitate the recruitment of intraepithelial dendritic cells to luminal antigens, resulting in an amplified immunological response and increased airway inflammation. Furthermore, RSV infection diminishes the expression of CLDN1 and OCLN, which are crucial for the barrier function of bronchial epithelial cells in both in-vitro and in-vivo models. RSV infection in children is reported to recruit neutrophils into the airways, which substantially decreases ZO-1 expression levels.⁷⁴

14. Restoring barriers: targeting barrier proteins for therapeutic interventions

The multifunctional roles of TJs in maintaining barrier integrity and regulating viral entry have led to the development of various drugs and inhibitors aimed at targeting these structures for antiviral therapies (Table 4). The Bowman-Birk inhibitor (BBI), a protease inhibitor sourced from soybeans, has shown anti-HIV-1 activity in human primary macrophages.²⁴⁶ HSV-2 infection promotes the sexual transmission of HIV-1. Inhibiting the ubiquitin-proteasome system prevents HSV-2-mediated protein degradation. BBI treatment in End1/E6E7 cells has been shown to enhance the expression of critical tight junction proteins, such as ZO-1, OCLN, and CLDN5.²⁴⁶ Further, peptides targeting CLDN4‘s extracellular loop 2 (ECL2) domain have shown potential for treating PRRSV infections. These peptides have low cytotoxicity and efficiently prevent PRRSV proliferation in a variety of pathogenic strains. They neutralize PRRSV particles, reducing viremia.⁷⁴ Similarly, CLDN1 has been demonstrated as an attractive antiviral target against HCV. The alicyclic dipeptide MA026 has been recognized as an irreversible tight junction opener, presumably via its interaction with CLDN1. This compound is considered a notable candidate for anti-HCV drug development. During drug screening for HCV treatments, researchers identified two piperazinyl benzene sulfonamides that effectively inhibit HCV entry into liver cells by blocking the interaction between CD81 and CLDN1, thus preventing viral infection.^74,261 In addition, JEV is reported to utilize the protease chymotrypsin to worsen BBB disruption by degrading TJ proteins such as CLDN5, ZO-1, ZO-2, and OCLN. However, the chymotrypsin inhibitor TY-51469 at appropriate concentrations was shown to prevent BBB breakdown.²³⁰ Monoclonal antibodies directed against the first and second extracellular loops of OCLN have demonstrated efficacy in inhibiting HCV infection in Huh7.5.1–8 liver cells in a dose-dependent manner.²⁶² Houttuynia cordata, a traditional medicinal plant, has also been shown to upregulate ZO-1 expression, thereby enhancing epithelial barrier function and providing resistance to influenza virus infection.²⁴⁵ Moreover, IL-22 treatment has been demonstrated to upregulate the expression of ZO-1 and OCLN in cells infected with HSV-2.²⁶³ This indicates its possible therapeutic use in enhancing tight junction integrity and inhibiting viral transmission, thereby emphasizing the significance of cytokine-based therapies in addressing viral infections.

Table 4.

List of therapeutic candidates.

Therapeutic candidate	Target	Therapeutic Category	Targeting Strategy	Current status	Barrier/tissue specificity	References
Cu/Zn superoxide dismutase	MMPs	Antioxidant enzymes	Inhibits MMP-2 and MMP-9 mediated degradation of laminin and claudin-5. Protects from HIV-1 gp120-induced BBB damage	Preclinical/Experimental	Blood-brain barrier	²²⁶
Alicyclic dipeptide MA026	CLDN1	Dipeptide	Interacts with CLDN1; irreversible tight junction opener	Notable candidate for anti-HCV drug development	Tight junctions	^74,75
Statins	Rho/ROCK Pathway	Drug	Pleiotropic effects including ROCK inhibition; endothelial protection. Anti-inflammatory and immunomodulatory effects during viral infections	Clinical trials (Phase II) in IAV patients	Blood-brain and blood-air barriers	^227–229
Chymotrypsin inhibitor TY-51469	Chymotrypsin	Inhibitor	Prevents BBB disruption due to JEV mediated degradation of CLDN5, ZO-1, ZO-2, and OCLN	Preclinical/Experimental	Blood-brain barrier	²³⁰
Memantine	NMDA receptor	Inhibitor	Reduces pathological activation of MMP-9. Protects from HIV-1 gp120-induced BBB damage	Used in treatment of Parkinson’s disease	Blood-brain barrier	²³¹
TLR3/dsRNA complex inhibitor	IL-6	Inhibitor	Reduces HIV-induced IL-6 mediated CLDN5 downregulation, monocytes adhesion and trans endothelial migration in-vitro	Preclinical/Experimental	Blood-brain barrier	²³²
Baricitinib	Janus Kinase (JAK)	Janus kinase inhibitor	Inhibits JAK1/JAK2, blocks the intracellular signaling of multiple pro-inflammatory cytokines like IL-6, IFN-γ that disrupt endothelial barriers	Clinical trials (Phase III) Approved for use in COVID-19 patients	Endothelial barriers	^233,234
miRNA-182	CLDN1	MicroRNA	Blocks claudin-1 expression and prevents HCV infection	Preclinical/Experimental	Tight junctions	²³⁵
Infliximab (anti-TNFα)	Cytokine-mediated signaling	Monoclonal antibody	Blocks cytokine-mediated signaling that increases endothelial permeability and downregulates TJ proteins	Preclinical/Experimental	Blood-air barriers	²³⁶
Tocilizumab (anti-IL-6R)	Cytokine-mediated signaling	Monoclonal Antibody	Improves oxidative stress and endothelial glycocalyx	Clinical trials (Phase III) in COVID-19 patients	Blood-brain and blood-air barriers	^237,238
Anti-claudin-1	CLDN1	Monoclonal antibody	Prevents HCV infection in in-vitro BMECs	Preclinical/Experimental	Blood-brain barrier	¹⁹⁰
Anti-JAM-A antibodies	JAM-A	Monoclonal antibody	Prevents transmigration of monocytes into CNS during HIV	Preclinical/Experimental	Blood-brain barrier	²³⁹
Anti-IP-10 antibodies	TNF-α	Monoclonal antibody	Reduces TNF-α, OCLN, CLDN5, and ZO-1. Inhibits JEV induced BBB disruption	Used in Clinical trial for ulcerative colitis	Blood-brain barrier	²³⁵
Anti-IL6R antibodies	OCLN and CLDN5	Monoclonal antibody	Inhibits IL6-mediated down-regulation of OCLN and CLDN5 in mouse model	Clinical trials for COVID 19 treatment	Tight junctions	²³⁵
Anti IFN-g antibodies	CLDN and ZO-1	Monoclonal antibody	Inhibits CLDN and ZO-1 disorganization. Reduces reovirus-induced BBB disruption in mouse model	Preclinical/Experimental	Blood-brain barrier	²⁴⁰
Dexamethasone	Cytokine-mediated signaling, tight junctions	Monoclonal Antibody; Steroids	Reduces degradation of tight junction proteins, enhances barrier function	Clinical trials (Phase III) Standard of care in severe COVID-19	Blood-brain and blood-air barriers	^241–243
PPAR agonist	PPAR-gamma (PPARγ)	Multimodal drugs	Reduces MMPs, restores JAM-A, OCLN, and ZO-1. Reduces HIV-1- or Tat-induced dysfunction of BBB	Used in treatment of type 2 diabetes	Blood-brain barrier	²⁴⁴
JAM-A antagonist peptide	C2 domain of JAM-A	Peptide	Inhibits JAM-A/leukocyte interaction	Preclinical/Experimental	Blood-brain barrier	²³⁵
Houttuynia cordata polysaccharides	ZO-1	Polysaccharides	Upregulates ZO-1 and provides resistance to IAV infection	Preclinical/Experimental	Epithelial barrier	²⁴⁵
Bowman Birk Inhibitor	Ubiquitin-proteasome system	Protease inhibitor	Anti-HIV-1 activity. Enhances the expression of ZO-1, OCLN, and CLDN5	Preclinical/Experimental	Tight junction proteins	²⁴⁶
Pegylated IFN-λ	Blood-brain barrier permeability	Recombinant protein	Modulates ZO-1 and CLDN5 in a protein synthesis and STAT1 independent manner. Restricts West Nile virus neuroinvasion	Clinical trials for HCV, HDV and COVID-19 treatment	Blood-brain barrier	⁹³
Fasudil	Rho/ROCK Pathway	Rho kinase (ROCK) inhibitor	Inhibits actin stress fiber formation, stabilizes junction proteins, and reduces endothelial cell contraction	Clinical trials (Phase II)	Endothelium	^247,248
Acalabrutinib	Bruton’s Tyrosine Kinase (BTK)	Second-generation BTK inhibitor	Targets active BTK in macrophages, reduces pro-inflammatory cytokines like IL-6, an effective indirect barrier-modulator	Clinical trials (Phase II) Improved clinical outcomes in COVID-19 patients	Lung injury in COVID-19 hypoxic patients	^249,250
Ibrutinib	Bruton’s Tyrosine Kinase (BTK)	Second-generation BTK inhibitor	Inhibits the function of B cell antigen receptors and cytokines	Clinical trials (Phase II)	Lung injury in COVID-19	^251–254
Minocycline	Anti-inflammatory	Second-generation tetracycline	Protects from JEV induced BBB damage, suppresses HIV replication	Clinical trial (Phase 2) in HIV patients	Blood-brain barrier	^255–257
Enzaustarin (LY-317615)	Protein kinase Cβ	Small molecule	Suppresses transmigration of activated T cells through an inflamed endothelial cell barrier, leading to induction of ZO-1, CLDN3 and CLDN5	In clinical trial for brain cancer treatment	Blood-brain barrier	²⁵⁸
Lithium	Wnt/β-catenin Pathway	Small molecule agonist	Lithium prevents gp120- and Tat-induced HIV neurodegeneration in-vitro	Preclinical/Experimental	Blood brain barrier	²⁵⁹
Dasatinib (Src inhibitor)	VE-Cadherin Signaling	Small molecule inhibitor	Inhibits VEGF-induced phosphorylation of Src in human retinal microvascular endothelial cells. Reduces enhanced permeability induced by direct DENV infection	Preclinical/Experimental	Endothelial barriers	^58,260

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15. Strategies for drug delivery across protective barriers

Many strategies have been developed over time to effectively deliver therapeutic agents across the barrier for the treatment of neurological disorders.⁸ These include invasive techniques such as catheter-based administration, direct brain injections, and the implantation of drug-loaded biodegradable polymers. Despite being successful in animal models, these methods are constrained in human settings because of patient variability and rapid elimination or degradation of drugs.²⁶⁴ Less invasive methods like intranasal administration use the olfactory and trigeminal pathways to circumvent the BBB. However, nasal mucosa variations and dose irregularities restrict its reliability. Strategies like hyperosmolar mannitol and focused ultrasound can transiently disrupt the BBB, but potentially permit the entry of harmful substances and raise safety concerns. To address this, drugs are frequently encapsulated in biocompatible nanoparticles that are capable of traversing the BBB.^264–266 Nanotechnological tools has been widely used to enhance the transport of retroviral drugs across BBB, with several experimental formulations showing promising results.^265,266 These strategies utilize nanoparticle size, composition, and surface functionalization to enhance drug transport across the BBB. Polymeric polybutylcyanoacrylate nanoparticles co-loaded with AZT and lamivudine demonstrated an increase in BBB permeability.²⁶⁷ In addition, saquinavir carrying transferrin-conjugated quantum rod nanoparticles has been reported to exploit receptor-mediated transport to cross an in-vitro BBB model.²⁶⁸ AZT-encapsulating spherical transferrin-coated PEGylated albumin nanoparticles made by the ultra-emulsification technique with chemical cross-linking by glutaraldehyde were able to pass the BBB by means of transferrin receptor-mediated membrane endocytosis.²⁶⁹ Magnetic liposomal nanoformulations of azidothymidine 5′-triphosphate have also demonstrated the ability to migrate across the BBB in-vitro.²⁷⁰ Additionally, a novel nanodrug, comprising an iron oxide nanoparticle coated with PMA amphiphilic polymer along with the antiretroviral peptide enfuvirtide, successfully traversed the BBB via passive diffusion.²⁶⁶ Recently, solid lipid nanoparticles (SLNs) have been demonstrated to enhance drug stability, minimize systemic toxicity, and provide controlled, sustained drug release. SLNs are capable of encapsulating both hydrophilic and lipophilic drugs. In contrast to polymeric nanoparticles. SLNs have low production costs, high biocompatibility, and enhanced patient compliance.²⁷¹ SLNs have shown enhanced brain-targeting efficacy for drugs such as nitrendipine, clozapine, and camptothecin, resulting in improved bioavailability and plasma half-life, while reducing toxicity.^271–273 Surface modifications, such as PEGylation and Pluronic F-68, facilitate evasion of reticuloendothelial system uptake and improve BBB penetration through receptor-mediated endocytosis.²⁷¹ SLNs additionally protects medicines from enzymatic degradation and enhance pharmacokinetics, making them ideal for CNS-targeted treatments. SLNs serve as a promising nanocarrier system for the delivery of drugs to the brain.^264,271,274 They may become a cornerstone of CNS therapies with continuous innovation due to their tailored delivery capabilities and improved pharmacological characteristics. Future advancements should focus on refining synthesis, optimizing sterilization, and enhancing formulation stability to address these challenges.

16. Conclusion and future perspective

Despite their anatomical and functional differences, all blood-tissue barriers share fundamental processes that control selective permeability and maintain homeostasis. Barrier dysfunction due to viral invasion frequently causes tissue-specific pathologies, which contribute to neurological problems, and immune-privileged organ damage. However, the dynamic features of blood-tissue barriers, are still poorly understood. A few important concerns about the changing characteristics of blood-tissue barriers include: How do blood-tissue barriers adjust to the metabolic needs of the local environment or react to viral invasion? What are the most prevalent signaling pathways that control the integrity, disruption, or repair of these blood-tissue barriers during viral pathogenesis? Understanding how small changes in barrier features like transporter function, transcytosis, and immune cell interactions contribute to disease development requires more investigation. Assessing whether barrier restoration completely restores function or leaves behind residual vulnerabilities is essential for effective long-term disease treatment. Similarly, the involvement of non-endothelial cells, such as pericytes, astrocytes, microglia, and trophoblasts, in the maintenance and restoration of barrier function during viral infections requires further examination.

Although blood-tissue barriers are primarily defensive, they also have profound medical consequences. Barrier compromise during infection often exacerbates disease severity. Their selective nature poses challenges for drug delivery in many areas, particularly in the brain, where the BBB restricts the entry of 98% of potential neurotherapeutics. For example, BBB’s restricted permeability and efflux mechanisms limit the efficacy of antiretroviral drugs against HIV in the CNS, necessitating alternative drug delivery strategies like nanoparticle formulations or intranasal administration. Taken together, a deeper understanding of blood-tissue barrier integrity is crucial in addressing viral pathogenesis. Understanding the molecular mechanisms governing the structure and function of blood-tissue barriers holds promise for therapeutic innovation. However, the dual role of blood-tissue barriers – as both protectors and obstacles – highlights the need for balanced therapeutic strategies. For instance, transiently disrupting tight junctions with hyperosmotic agents can enhance drug delivery to the brain but also heighten the risk of neuroinflammation. Therefore, comprehensive research into blood-tissue barrier biology and viral pathogenesis is essential for designing targeted therapies that preserve barrier function while overcoming viral persistence.

Acknowledgment

Apoorva acknowledges the support provided by the Department of Science and Technology (DST), Ministry of Science and Technology, Govt. of India, through the DST-INSPIRE Fellowship Programme (IF210467). SKS acknowledges the funding support provided through the Institutions of Eminence (IoE-6031) Scheme of Banaras Hindu University by the University Grant Commission (UGC), India; and Institutions of Eminence (No./IoE/2023-24/12/FRP) Scheme of the University of Delhi, New Delhi, India.

Funding Statement

Disclosure statement

No potential conflict of interest was reported by the author(s).

Credit authorship contribution statement

Apoorva: Conceptualization; Writing – original draft preparation; Visualization. Sunit K. Singh: Conceptualization; Writing – review and editing; Resources; Supervision.

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PERMALINK

Pathogenic breaches: how viruses compromise blood-tissue barriers

Apoorva

Sunit K Singh

ABSTRACT

1. Introduction

Figure 1.

Table 1.

2. Endothelial cells: gatekeepers of blood-tissue barriers

Figure 2.

Table 2.

Table 3.

3. Tight junctions: flexible regulators of blood-tissue barriers

4. Pericytes: essential vascular regulators

5. Basement membrane: a key component of blood-tissue barrier architecture

6. Glial cells: architectural support to the blood-brain barrier

7. Tissue-specific adaptations

8. Viral routes and pathways to disrupt barrier function

8.1. Viral infiltration tactics

8.2. Structural sabotage of tight and adherens junction

Figure 3.

8.3. Cytokines and barrier disruptions

8.4. Direct cellular damage leading to disruption of barrier integrity

8.5. miRNA-mediated dysregulations leading to barrier disruptions

9. Viruses traversing across blood-brain barrier

9.1. Flaviviruses

Figure 4.

9.2. Retroviruses

9.3. Alphaviruses

9.4. Rhabdoviruses

9.5. Coronaviruses

10. Viruses traversing across blood-placental barrier

10.1. Flaviviruses

Figure 5.

10.2. Retroviruses

11. Viruses traversing across blood-retinal barrier

11.1. Flaviviruses

11.2. Herpesviruses

11.3. Retroviruses

12. Viruses traversing across blood-testis barrier

12.1. Paramyxoviruses

12.2. Retroviruses

12.3. Coronaviruses

12.4. Flaviviruses

13. Viruses traversing across blood-air barrier

13.1. Orthomyxoviruses

Figure 6.

13.2. Coronaviruses

13.3. Paramyxoviruses

14. Restoring barriers: targeting barrier proteins for therapeutic interventions

Table 4.

15. Strategies for drug delivery across protective barriers

16. Conclusion and future perspective

Acknowledgment

Funding Statement

Disclosure statement

Credit authorship contribution statement

References

ACTIONS

PERMALINK

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