Unravelling the interaction between Influenza virus and the nuclear pore complex: insights into viral replication and host immune response

Abstract

Influenza viruses are known to cause severe respiratory infections in humans, often associated with significant morbidity and mortality rates. Virus replication relies on various host factors and pathways, which also determine the virus’s infectious potential. Nonetheless, achieving a comprehensive understanding of how the virus interacts with host cellular components is essential for developing effective therapeutic strategies. One of the key components among host factors, the nuclear pore complex (NPC), profoundly affects both the Influenza virus life cycle and the host’s antiviral defenses. Serving as the sole gateway connecting the cytoplasm and nucleoplasm, the NPC plays a vital role as a mediator in nucleocytoplasmic trafficking. Upon infection, the virus hijacks and alters the nuclear pore complex and the nuclear receptors. This enables the virus to infiltrate the nucleus and promotes the movement of viral components between the nucleus and cytoplasm. While the nucleus and cytoplasm play pivotal roles in cellular functions, the nuclear pore complex serves as a crucial component in the host’s innate immune system, acting as a defense mechanism against virus infection. This review provides a comprehensive overview of the intricate relationship between the Influenza virus and the nuclear pore complex. Furthermore, we emphasize their mutual influence on viral replication and the host’s immune responses.

Introduction

Influenza viruses are members of the family Orthomyxoviridae, are further characterized as types A, B, C, and D. Two types, types A and B, cause acute respiratory tract infections in humans. IAVs contain 10 viral proteins, designated as RNA polymerase subunits (PA, PB1, and PB2), glycoproteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein M1, membrane protein (M2) and non-structural protein (NS1), and nucleoprotein export protein (NEP). These proteins play essential roles in the replication and infection processes of the virus within host cells. The two viral glycoproteins i.e., HA and NA serves as the primary targets for the protection against Influenza virus infection and immunization. IAV undergoes frequent antigenic changes due to random mutations or genetic reassortment between different strains of the virus [6]. These changes help the virus to evade the host immune system and are responsible for sudden epidemic outbreaks and global pandemics. Therefore, the influenza vaccine must be reformed annually to incorporate the antigenic changes in viral surface proteins [41]. The potential for new viral strains with no existing immunity in the population still poses a risk. However, the increasing number of cases of drug resistance caused by all licensed drugs is a serious matter of concern for the healthcare sector [42, 44]. In light of the continuing threat of Influenza virus infection and the current state of prevention and treatment, it is necessary to explore more and understand the detailed mechanism of influenza pathogenesis.

Influenza viruses possess an enveloped structure and harbor negative sense, single-stranded and segmented RNA genome, consisting of eight RNA segments [49, 71]. These RNA segments are responsible for encoding crucial components such as RNA polymerase subunits, viral glycoproteins, nucleoprotein, matrix protein, membrane protein, and the non-structural protein. Influenza A viruses are categorized according to their surface glycoproteins, known as HA and NA. HA facilitates the attachment to sialic acid (SA) receptors found on host cell membranes, while NA, an integral membrane glycoprotein with sialidase activity, aids in releasing mature virions during the final stage of replication [11, 48]. HA and NA work together in a 4:1 ratio due to co-evolutionary adaption [52]. This cooperation ensures HA binding and NA removal of SA [24, 47]. The segmented genome and the frequent mutations occurring during replication across various hosts contribute to both regular outbreaks and sporadic pandemics [40, 43, 45, 46]. In humans, the Influenza virus undergoes replication within the epithelial cells of the upper respiratory tract (URT) [87]. The virus can reproduce in the lungs and trachea, among other LRT tissues [62]. Several crucial steps are taken when an enveloped virus enters cells from the extracellular environment [8, 86]. The HA protein enters into the host cell by binding to SA receptor located on the surface of epithelial cells [11, 100]. Due to the acidic environment of an endosome, the virus opens its M2 ion channel within it after internalization [93, 95]. The viral RNA is released into the cytoplasm of the host cell when protons enter the virus and fuse the viral and endosomal membranes [31]. After viral RNA is transported into the cell nucleus, transcription occurs within this area [21]. Viral replication proceeds through the translation of complementary RNA, which serves as a positive-sense intermediate, into positive-sense viral mRNA. Subsequently, after undergoing capping and polyadenylation, mRNA is transported to the cytoplasm for translation [94]. Restoring of NP protein, PB1, PB2 and PA that are newly made viral RNA-dependent RNA Polymerase and PB1 into the nucleus that restores viral RNA production [17, 51, 91]. During the last stages of infection, M1 and nuclear export proteins bind to viral RNA and move it from the nucleus to the cytoplasm [10].

After acquiring ribonucleoproteins (RNPs), the eight developing RNA segments are bundled for budding egress [1]. Numerous viral proteins have the potential to be targets for vaccinations or antivirals, and some can potentially affect how the immune system reacts to an infection [19, 59, 65].

It is known that viruses rely on host cellular machinery for multiple stages of their life cycle [58, 68, 79]. Elucidating the complex interplay between the Influenza virus and its host is essential [36, 63, 97, 98]. Investigating the relationship between the virus and the host reveals the possible treatment targets and the molecular mechanisms underlying viral pathogenesis [9, 12, 37, 67, 101]. The nuclear pore complex is a crucial component out of all host variables that affect the import and export of virus particles during infection [53, 88, 102]. The nuclear pore complex, its function, also the role it plays, and how it interacts with the Influenza virus during infection are discussed (Fig. 1).

Fig. 1.

a Diagrammatic illustration of Influenza virus structure and its key components b Schematic representation showing crucial steps of the Influenza virus life cycle

Nuclear pore complex (NPC)

The NPC is one of the most substantial protein assemblies within human cells and has a molecular mass of 110 MDa [56]. It consists of numerous copies of approximately 30 distinct proteins referred to as nucleoporins (Nups). The nuclear pore complex is composed of two primary functional sections: the central structure, which is encased in the plane of the nuclear envelope, and the peripheral structure, which extends its reach into the nuclear interior and cytoplasm. An eightfold symmetrical cylindrical structure encloses the primary nuclear transport channel, serving as a molecular screen to regulate the bidirectional movement of different metabolites. The asymmetrical filamentous structures that make up the peripheral NPC extensions link the core structure to its molecular surroundings, which can be found either inside the nucleus or in the cytoplasm. The nuclear basket structure in the nucleus links the NPC to processes related to nuclear metabolism, such as mRNA synthesis and genome intake [78]. Specialized filaments on the other side of the membrane extend into the cytoplasm, directing export cargo to the machinery involved in protein synthesis and directing incoming cargo from the cytoskeleton to the interior of the nucleus. NPCs are considered to be the gatekeepers of the nucleus and facilitate almost all transport between the nucleoplasm and cytoplasm [25] (Fig. 2).

Fig. 2.

Critical components of the Nuclear Pore Complex (NPC) are depicted, emphasizing their pivotal roles in facilitating the import and export of various proteins and nucleic acids across the nuclear membrane. These components enable complex regulatory processes required for cellular activity, enabling precise control over molecular traffic between the nucleus and the cytoplasm

Nucleocytoplasmic transport

The nucleocytoplasmic shuttling of viral proteins is one of the major transport mechanisms for importing viral RNA into the cell [29, 55]. Certain viral proteins possess nuclear export signals (NESs) that enable their export from the nucleus to the cytoplasm [69]. The translocation of these NES-containing viral proteins through the nuclear pore complex is mediated by their interactions with exportin proteins, including CRM1 (chromosome region maintenance 1) [20]. The FG repeat and nucleoporins both aid in the selective export of viral proteins [80]. For the virus to assemble, the newly created vRNPs need to be transferred to the cytoplasm after transcription and viral replication in the nucleus [32, 38]. Viral nucleoproteins and viral RNA segments interact with exportins, such as CRM1, to facilitate the nuclear export of vRNPs [22, 70]. The FG repeats and nucleoporins give the vRNPs a way out of the nucleus. Similary, the Influenza virus has also developed several strategies to take advantage of the NPC. Viral proteins that interact with nucleoporins, such as NS1 and NEP/NS2, modify the nuclear transport mechanism [74, 75, 91]. These interactions control the location of viral components, alter the host cell's antiviral responses, and guarantee effective viral reproduction and immune system evasion [13, 35, 90]. A viable strategy to combat influenza pathogenesis may involve investigating the nuclear pore complex and influenza virus interactions during virus replication [89].

Interaction between Influenza virus and nuclear pore complex

Nuclear proteins are necessary for the replication of the majority of viruses with nuclear and cytoplasmic replication [52]. Several medications that target nuclear transport of viral proteins have been shown to prevent the virus from spreading. It implies that critical elements of the nucleus of infected cells are viral proteins.

The nuclear pore complex is altered by the number of negative-strand RNA viruses through a variety of methods [34]. The purpose of these modifications is threefold: first, they enable interaction with nuclear proteins associated with viral replication in the cytoplasm; second, they influence the immune response against viruses by blocking transcription factors from entering the nucleus; and third, they repress the exchange of cell mRNA to the cytoplasm, decreasing the opposition for translational machinery and subsequently bringing down the translation of proteins associated with antiviral reactions [34]. The recognition that disrupting the import–export process serves as a checkpoint for virus development makes it unsurprising that viruses induce the degradation of specific NPC components through their viral proteases. The nuclear envelope (NE), which is made up of a double membrane containing nuclear pore complexes and multiple copies of Nups, is necessary for the import and export of viral proteins [72]. The nuclear pore complex facilitates the bidirectional transport of large molecules, ribosomal parts, viral proteins, and diverse RNA molecules (such as mRNA, rRNA, tRNA, and miRNA) between the nucleus and cytoplasm, originating from cellular and viral origins [34].

Recent studies have uncovered a significant involvement of nuclear pore complex proteins in the replication and transcription process of Influenza virus [30, 34]. The viral vRNPs, viral proteins, and replication machinery are imported into the nucleus to establish viral replication complexes [85]. Various nucleoporins such as Nup98, Nup153 and importin proteins, such as Importin α and Importin β, play a crucial role in facilitating the nuclear import process that enhances viral transcription and replication [15, 26, 81]

After viral internalization, and vRNP release in the cytoplasm, importin α: β heterodimer carried vRNPs into the nucleus via nuclear pore [74]. Importin- α connects with importin- β after identifying the nuclear localization sequences (NLSs) on nucleoprotein [7, 50, 73]. Newly synthesized polymerase subunits need to assemble into a catalytically active hetero-trimer in the nucleus after initial transcription and translation [92]. The binding of importin isotypes such as importin-1 (IMP-1), importin-3 (IMP-3), importin-5 (IMP-5), and importin-7 (IMP-7) by newly synthesized PB2 has been demonstrated. PA and PB1 translocate to the nucleus through the binding of importin Ran-binding protein 5 (RanBP5) [57, 76]. Heat Shock Protein 90 (HSP90), Phospholipid scramblase 1 (PLSCR1), translation elongation factor 1 delta (eEF1D), and LYAR are examples of factors that can have an impact on the nuclear import of ribonucleoprotein (RNP), which in turn can have an impact on viral replication [64]. In addition to this, the host nuclear machinery is necessary for the transit of vRNP. According to earlier studies, nucleoporins such as NUP98, NUP93, NUP214, and NUP153 interact directly with viral proteins to aid in their nuclear import [61, 82]. These nucleoporins have also been linked to functions in Influenza virus replication [39] (Table 1). Additionally, the FG repeat-containing nucleoporins lining the central channel of the NPC form a permeability barrier that regulates the translocation of molecules, including viral components [83]. The relationship between specific nuclear proteins and Influenza virus infection, as well as their function in Influenza virus replication and their processes, have not much known [77]. Further studies could focus on explaining the precise mechanism underlying these interactions and their impact on viral pathogenesis [5, 96].

Table 1.

Host factors subverted by Influenza virus to facilitate transport through NPC

Host factors	Function	References
Importin–α	Import	[27, 73]
Importin–ß	Transport NLS	[74]
KPNB 1	Binds with NLS and help in nuclear import	[50]
CRM-1	Nuclear export of mRNA	[20]
NFX-1	Nuclear import	[30]
NUP 93	Nuclear export of vRNP	[26]
NUP 98	Docking site for mRNA export factors	[15]
NUP 153	Intracellular transport and cell structural integrity	[50, 61]
NUP 62	Nuclear export machinery	[66]
NUP 85	Interacts with PB1 & PB2, promote replication	[57]
NUP 214	Interacts with NS2 protein and help in replication	[82]
p15	Nuclear export	[80]
Rae 1	Nuclear export	[80]

Displays a range of host nuclear elements implicated in influenza infection to date. Advances have been achieved in recognizing these nuclear factors and understanding their roles in the virus’s entry into the nucleus. However, numerous host factors and their corresponding molecular details remain unexplained

The interaction between the Influenza virus and the nuclear pore complex is crucial for viral pathogenesis. The nuclear import of viral components allows the establishment of viral replication complexes within the nucleus. The selective export of vRNPs ensures the transport of newly synthesized viral genetic material to the cytoplasm for viral assembly. Disruption of the Influenza virus-NPC interaction can significantly impair viral replication and reduce pathogenicity. By manipulating the nuclear pore complex, the Influenza virus can evade the host's immune responses, and the interaction of viral proteins with nuclear factors can modulate the expression of host antiviral genes and interfere with the nuclear import/export of immune signaling molecules [4]. Comprehending these pathways can facilitate the formulation of strategies aimed at augmenting host immune responses and restricting viral replication [33].

Host immune response to Influenza virus entry through the NPC

The Influenza virus enters the body through the NPC without interference from the host immune system [99]. Cells have evolved sophisticated defense mechanisms to recognize and destroy viral intruders, including those that attempt to exploit the nuclear pore complex. The Influenza virus enters the body through the nuclear pore complex, and in this section, we look at some of the most crucial aspects of the host's defensive mechanism [28, 77].

Pattern recognition receptors (PRRs) and innate immunity

The initial line of defense for the host after the Influenza virus reaches the nucleus through the NPC is the innate immune system [62]. The ability to recognize viral invasion requires pattern recognition receptors or PRRs. Some of the most significant PRRs that harbor Influenza virus packaged components are toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and nucleotide-binding oligomerization domain (NLRs).

The interaction of RLRs, such as RIG-I and MDA5, with Influenza virus RNA sets off a signaling cascade that activates nuclear factor-B (NF-B) and interferon regulatory factors (IRFs). Type I interferons (IFNs) and pro-inflammatory cytokines are produced as a result. Because type I IFNs possess antiviral response,they can also cause nearby cells to enter an antiviral state, reducing their susceptibility to Influenza virus infection (Figs. 1, 2, 3)..

Fig. 3.

Schematic representation depicting role of different innate immune responses as primary defense against viral invaders. This host line of defense is crucial for neutralizing pathogenic threats and maintaining cellular integrity

Nuclear pore complex surveillance

To detect any unexpected or unauthorized nuclear transit, the NPC is outfitted with tracking equipment. The immune system has been linked to nucleoporins like Nup98 which can modulate antiviral responses through its interaction with RanBP2, a cellular protein necessary for the post-translational modification known as SUMOylating [54]. This gives rise to the possibility that the NPC may actively assist in the host's defense mechanism against viral invasion.

Restriction factors

Numerous restriction factors found in cells stop viruses from multiplying. Certain components are exclusive to the nucleus and could be significant when the Influenza virus attempts to replicate its genome within the host's nucleus. For instance, it has been demonstrated that the host protein MX1 binds to viral ribonucleoproteins to prevent Influenza virus RNA from replicating in the nucleus.

Immune signaling

The replication of the Influenza virus after it enters the cell's nucleus and the subsequent signaling pathways that are activated as a result can all affect the immune system [18]. For instance, viral RNA and proteins in the nucleus may cause the DNA damage response (DDR) pathway to be activated. As a result of this, P53 and other proteins involved in apoptosis and antiviral defense may be activated.

Inflammatory response

The release of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) is a hallmark of the inflammatory response that cells may develop in response to viral invasion [27]. These cytokines can entice immune cells to the site of the infection and strengthen the body's antiviral defenses [14].

As previously stated, the synthesis of interferons, proinflammatory cytokines, and interferon-stimulated genes in the innate antiviral immune response relies on the nuclear translocation of crucial signal transducers within the innate immune system [27]. Predictably, different nucleoporins and/or nuclear transport receptors will interact with signal transducers such as IRF3, NF-B (p50/p65), and STATs. When pattern-recognition receptors are activated, this connection helps transfer them via nuclear pore complexes and from the cytoplasm to the nucleus.

Interferon regulatory factor 3 (IRF3)

IRF3 is a critical transcription factor in several innate immune pathways, such as TLR3 signaling, cGAS/STING signaling, and RIG-I-like receptor signaling. Upon the activation of pattern recognition receptors, IRF3 initiates the transcription of IFN-I genes. Importin-1, importin-3, and importin-4 are the three identified nuclear transport receptors that facilitate the nuclear transportation of IRF3 [28].

Nuclear factor kappa B (NF-kB)

Another important downstream signal transducer, NF-kB(p50/p65), transcriptionally promotes IFN-I and proinflammatory cytokines, which in turn activates PPR. Importin-1, Importin-3, and Importin-4 facilitate the transportation of molecules into the nucleus, relying on specific nucleoporins including Nup88, Nup214, Nup98, Nup153, RanBP2/Nup358, and POM121 [23]. Certain mutations involving chromosome translocations lead to the fusion of Nups with various proteins, affecting the movement of NF-kB (p50/p65) between the nucleus and cytoplasm, thereby influencing the initiation of innate immune responses. The nuclear factor NF-kB's activity can be reduced by CRM1, the protein that regulates p65 nuclear export. It has been proposed that increasing the expression of Nup62 leads to the stabilization of overexpressed Nup88, promoting its interaction with NF-kB (p65) and triggering inflammatory signaling. POM121 has been shown in another study to block the nuclear translocation of phosphorylated p65 (phos-p65), which in turn suppresses the inflammatory response in macrophages. Another study claimed that in response to TNF (tumor necrosis factor) stimulation, Nup153, a part of the nuclear pore basket, and RanBP2/Nup358, one of the primary cytoplasmic filaments on the nuclear pore complex, created a complex (RanBP2/Nup358-RanGDP-Nup153-I-B-SUMO). During nuclear import, this complex enables the IB site to connect to NF-kB (p50/p65). In turn, IB-binding conceals the DNA-binding domain and nuclear localization signal of NF-kB (p50/p65), downregulating innate immune responses.

Signal transducers and activators of transcription (STATs)

Interferon-stimulated gene expression is crucially induced by the nucleocytoplasmic trafficking of STATs (like STAT1 and STAT2) to prevent viral replication and assembly. In reaction to cytokine stimulation, tyrosine-phosphorylated STAT dimers employ importins to enter the nucleus. This process is usually carried out in two ways. Through FG, latent unphosphorylated STATs adopt energy-free, karyopherin-independent translocation methods that are not triggered by cytokines in the second pathway [3]. So far, it has been shown that a variety of transport receptors and nucleoporins assist the nucleocytoplasmic trafficking of phosphorylated or unphosphorylated STATs. The amount of STATs gathered following cytokine stimulation is typically regulated by how long they remain in the nucleus rather than how quickly they enter it. Research indicates that different phosphatases, such as TC45 (T cell protein tyrosine phosphatase) and SHP2 (SH2 domain-containing protein tyrosine phosphatase 2), influence how long phosphorylated STAT1 remains active inside the nucleus. Following dephosphorylation, STAT1's DNA-binding domain binds to CRM1, facilitating its export back to the cytoplasm for subsequent activation-inactivation cycles.

Regarding the IFN-I signaling pathway, another vital type of transcription factor is STAT2; unlike other STATs, the constitutive binding partner of STAT2 is the transcriptional activator IRF9. Upon activation with IFN-I, phosphorylated STAT2 is integrated into the ISGF3 complex, which is then transported to the nucleus. Thus, for active STAT2 to enter the nucleus, STAT1 is also essential.

It was stated earlier, that numerous nuclear pore proteins and nuclear transport receptors regulate signal transducer nucleocytoplasmic shuttling. The host's innate immune response to viral infection depends on this control. As a result, it makes sense that some viruses will alter the nucleocytoplasmic transport mechanism to get past the body's natural antiviral defenses. During entry through the NPC, the Influenza virus interacts complexly and dynamically with the host immune system. The host's innate immune system produces strong pro-inflammatory reactions and acts as a rapid first line of defense, but viruses have also devised means of avoiding detection and manipulating host defenses [2, 80, 82]. Below are some major elements of this interaction that are covered:

Immune evasion

The Influenza virus has evolved several defenses against human immunological vigilance [16]. It may undergo reassortment or antigenic change, for example, enabling it to evade detection by earlier antibodies. The virus can also prevent the host from producing type I interferons, which are important antiviral cytokines.

Viral accessory proteins

Influenza viruses encode two auxiliary proteins, PB1-F2 and Non-structural protein 1 (NS1), which can suppress host immune responses. Reducing the activation of RIG-I and other PRRs, especially NS1, can lower the generation of interferons [60].

Host adaptation

The degree to which various Influenza virus strains adapt to their hosts varies. Certain strains are more adept at replicating their DNA within the nucleus without triggering a powerful host response. This adaptability aids in the virus's transmission to a range of hosts, including humans, pigs, and birds.

Host Immune evasion countermeasures

The host has created defenses to improve immune surveillance in response to viral evasion techniques. For instance, by concentrating on viral components in the nucleus, cellular proteins like TRIM22 and promyelocytic leukemia (PML) protein might prevent the production of the Influenza virus.

Cytokine storm

An uncontrolled inflammatory reaction, frequently referred to as a "cytokine storm," can happen in severe cases of influenza infection. This heightened immune response is linked to serious illness outcomes and can result in tissue damage. Research is still being done to determine what causes cytokine storms when influenza is present.

It seems quite clear after understanding the interactive mechanism between influenza and nuclear pore complex and also various aspects of host immunological response that Influenza virus entry through the nuclear pore complex is a diverse and finely controlled mechanism. The interaction of the innate and adaptive immune systems, as well as the development of an antiviral state and the management of inflammation, is crucial components of the host's defense against influenza infection [16].

Conclusions

The potential target for antiviral treatments lies in the interaction between the Influenza virus and the nuclear pore complex (NPC). Preventing viral replication and dissemination could be achieved by disrupting the nuclear import/export of viral components or specifically targeting nucleoporins involved in viral transport. Current intensive research is deeply examining the molecular processes that control the interaction between the Influenza virus and the NPC. This involves examining the specific link between viruses and nucleoporins, the impacts of post-translational modifications in nucleoporins, and the results of viral influence on nucleocytoplasmic transport. Utilizing proteomics, structural biology, and advanced imaging methods aims to gain a comprehensive understanding of this intricate relationship. This knowledge is crucial for developing specialized therapeutic strategies, enabling the interruption of viral-nucleoporin interactions to halt the nuclear import/export of viral components. While antiviral drugs targeting the NPC are in development, further exploration in this field is essential not only for combatting influenza but also for advancing global public health and broadening the scope of antiviral therapeutic research to address other viral infections.

Future perspectives

The interplay between Influenza virus and the nuclear pore complex is a very promising area of research, which offers several opportunities for exploration in the domain of drug development. Further investigation into this interaction reveals some promising prospects: Initially, identifying distinctive viral host factors beneficial for targeted treatment could establish new drug targets, potentially enhancing antiviral therapy. Moreover, it can coincide with breakthroughs in imaging and microscopy enabling the real-time visualization of virus-NPC interplay elucidating the viral pathogenesis and immune evasion mechanisms. In addition to employing computational modelling and network analysis through the systems biology approach we can uncover regulatory networks and new therapeutic options along with host factors revealing comprehensive insights into the treatment strategies. Leveraging insights into NPC-mediated viral replication and the host immune system can pave next-gen vaccines that are more adapted in combating diverse influenza strains and mitigating future outbreaks. Ultimately, enhancing future effectiveness, interdisciplinary collaboration among virologists, immunologists, structural biologists, and computational scientists is crucial to drive innovation, translate discoveries into clinical applications and also reduce the global burden of influenza. Embracing these approaches and fostering interdisciplinary cooperation will accelerate the fight against Influenza virus interactions, leading to improve health outcomes.

Abbreviations

CRM 1

Chromosome region maintenance 1

HA

Haemagglutinin

HSP-90

Heat shock protein 90 (HSP90)

IAV

Influenza A virus

IFN

Interferons

IMP

Importin

LRT

Lower respiratory tract

M1

Matrix protein

M2

Membrane protein

NA

Neuraminidase

NEP

Nuclear export protein

NES

Nuclear export signals

NLS

Nuclear localized signals

NPC

Nuclear pore complex

NP

Nucleoprotein

NS 1

Non-structural protein

NUP

Nucleoporin

PLSCR1

Phospholipid scramblase 1

RNA

Ribonucleic acid

RNP

Ribonucleoprotein

SA

Sialic acid

TLR

Toll like receptor

URT

Upper respiratory tract

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.