Biosafety and mental health: Virus induced cognitive decline

Highlights

• •Infection induced cognitive decline are persistent threat to people's health.
• •Infection induces neurotoxicity and neuroinflammation which contributes to cognitive decline.
• •Targeting CDK5 or other critical pathway may provide new solutions to alleviate infection induced cognitive decline.

Abstract

Biological agents threats people's life through different ways, one of which lies in the impairment of cognition. It is believed cognitive decline may result from biological agents mediated neuron damage directly, or from the activation of the host immune response to eradicate the pathogen. However, direct linkage between infections and cognitive decline is very limited. Here we focus on the mechanisms of how different biological virus or they induced systemic and local inflammation link to the cognitive impairment, focusing on the roles of activated microglia and several molecular pathways mediated neurotoxicity.

1. Introduction

Recently, many “black swan” incidents occur in the field of biosafety. The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the acute hepatitis of unknown cause in children, the pandemic caused by monkeypox virus are all serious threat to people's health. Meanwhile biological weapon threats, and laboratory biosafety concerns including the potential risks associated with not only cytometry instrumentation and samples, but also the people working with them, all call for urgent prevention or intervention strategies. Traditional therapies against biological threats still have shortcomings. The pathological mechanisms by which biological agents threats human health are of great interesting to be investigated (Fig. 1).

Fig. 1.

Infections cause cognitive impairment and the molecular mechanisms involved. Neurotoxic proteins produced during the infection can cause neurotoxicity to neuronal cells and affect neuronal function. Meanwhile, excessive systemic or local immune responses caused by infection can produce a variety of cytokines that can disrupt the blood–brain barrier or directly affect neuronal activity. Aberrant neuronal function ultimately leads to cognitive deterioration. There are various molecular mechanisms involved in the disruption of neuronal function, such as CDK5, CCR5, autophagy, complement pathways and others.

Biological agents threats people s life through many different ways. It is noteworthy that infections play a cofactorial role in inducing neurodegenerative diseases [1], [2]. For example, more than 50% of patients who survive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae. Cognitive deterioration is considered to be a common manifestation of a range of mental illnesses. Impairments in cognitive function are mainly manifested in the significant deterioration of working memory, episodic memory, information processing speed and attention during ageing. Cognitive decline compromises the quality of life, mental health and work status of patients. Cognitive decline is not only limited to those infections primarily affecting the central nervous system (CNS) [3], [4]. Many other acute infections and specific chronic infectious conditions such as human immune deficiency virus, the herpes virus family, hepatitis C virus, Lyme borreliosis, Helicobacter pylori, periodontitis and emerging pathogens like SARS-CoV-2 have been reported to cause cognitive impairment [5], [6]. Increasing reports showed that infections are generally related to uncontrolled immune response which lead to many bystander complications including neurotoxicity and cognitive decline. Unfortunately, the mechanisms responsible for these impairments remain to be determined [7], [8]. The infection of SARS-CoV-2, neurological dysfunction can ensue due to direct viral encephalitis or neuroinflammation (including damage to blood–brain barrier integrity) [9], [10]. The causal relationship between specific pro-inflammatory cytokines, mood symptoms, and cognitive decline is firmly established [11]. Collecting data on coronavirus disease 2019 (COVID-19) showed that a subset of individuals consistently exhibited markers of inflammation following the resolution of acute COVID-19 infection, suggesting hyperinflammation is an amenable cause of cognitive impairment [12]. In this review we analyzed and explored the correlation between cognitive decline and biosafety-related infection from an inflammatory point of view, focusing on the main molecular mechanisms.

2. Infection induced neurotoxicity and cognitive decline

Many pathogens including virus and bacterials are related to cognitive decline. From these, we selected virulently infectious agents, such as SARS-CoV-2, HIV and zika, to describe the relationship between pathogenic infection and cognitive deterioration in terms of both neurotoxicity and neuroinflammation.

2.1. SARS-CoV-2 induced neurotoxicity and cognitive decline

The clinical symptoms of SARS-CoV-2 infection range from asymptomatic to severe respiratory failure, with most patients also experiencing fever, cough and fatigue, and so on [13]. In addition to damage to the respiratory system, SARS-CoV-2 infection also causes damages to organs such as the brain, heart, kidneys, liver and intestines, and a growing number of studies have shown that SARS-CoV-2 infection caused cognitive decline in the central nervous system [14].

MRI results of the patient's brain showed reduction of brain volume, grey matter thickness and tissue contrast in the orbital cortex and parahippocampal gyrus associated with odour and event memory [15]. Meanwhile, MRI results also showed some patients had abnormal medial temporal lobe signal and non-confluent multifocal white matter high signal lesions on the FLAIR phase. In other patients, extensive and isolated white matter microbleeds occured, and the microstructure of hippocampus also changed [15], [16]. White matter damage, hemorrhagic lesions and damage to the hippocampus have been shown to be associated with cognitive decline [17]. The mini-mental state examination (MMSE), MoCA, Hamilton Rating Scale for Depression, FIM and other tests have revealed cognitive decline in the majority of patients [18].A return survey of patients being discharged after 3–4 months found that over 80% of patients had cognitive impairment, with the greatest impact on verbal learning and executive skills [19].

As for the mechanisms by which SARS-CoV-2 induced cognitive decline, reports showed that it can invade the central nervous system through the blood–brain barrier or olfactory mucosa [20], [21]. Breach of the blood–brain barrier facilitates the chance of SARS-CoV-2 entering into the central nervous system [22].

SARS-CoV-2 infects astrocytes by binding to NRP1 or ACE2 deteriorating the cognition of brain through impairing neuronal function and viability, altering energy metabolism, promoting the secretion of neurotoxic factors [23]. It has been shown that infection with SARS-CoV-2 virus results in ischemic damage to the white matter of the brain, which results in abnormal clearance of amyloid beta in the brain, promoting the accumulation of beta-like amyloid in the brain and producing neurotoxicity [24], [25]. SARS-CoV-2 leads to a sustained loss of myelinated axons due to a steady decline in oligodendrocytes, which impairs interneuronal bioelectrical signals transduction and neuronal activity [26]. Unlike the above, SARS-CoV-2 can also directly invade neurons causing metabolic disturbances and promoting apoptosis. It also can induce hypoxia to promoting uninfected neurons apoptosis [20].

2.2. HIV-associated neurocognitive disorder (HAND)

HIV-associated neurocognitive disorder (HAND) was recognized at the beginning of the AIDS epidemic and is a direct manifestation of HIV infection of the central nervous system [27], [28]. Although antiretroviral therapy (ART) for HIV has reduced mortality and prolonged life expectancy [29], nearly half of patients with HIV-related neurocognitive impairment remain after treatment [30], [31], [32]. The pathogenesis of HAND progresses slowly and patients present clinically with impairments in cognition, behavior, motor and autonomic functions. In the early period of the disease, the patient's attention, memory and executive functions are impaired and with the progress of the disease, the patient suffers from impaired consciousness and motor impairment, eventually progressing to dementia and even fatality [33]. Studies have shown that HIV damages the brain's corpus striatum, the dentate gyrus and the C3 region of the hippocampus, which are responsible for executive functions, learning and memory respectively [33].

Depending on the severity of the neurocognitive disorders, HIV-related neurocognitive disorders are classified as asymptomatic neurocognitive impairment (ANI), mild cognitive impairment (MND), HIV-associated dementia (HAD) [28], [34], [32]. ANI is defined as having at least two impaired cognitive abilities (including attention, memory, speed of handling information, learning, language, visual perception, abstract/executive function and motor skills) with prerequisite condition patients without other diseases. patients with ANI are not affected in daily life [28]. MND interferes with daily life slightly, and exhibits mild impairments in memory, attention, executive ability, fluency in language. The characters of MND exhibit two or more cognitive impairments in the absence of other diseases [34], [35]. HAD is defined as the presence of at least two or more symptoms of significant cognitive impairment, and pronounced interfere with daily life without other diseases. It is mainly characterized by progressive subcortical dementia. Moreover, the brain will atrophy with severe memory and executive skills impairment [34].

There are different ways in which the HIV virus enters the central nervous system and Trojan horse theory proposes that the virus enters the central system with infected monocytes/macrophages [36]. Besides, Viruses can invade endothelial cells at the blood–brain barrier and enter the central nervous system via gp120-mediated transcytosis [37]. Furthermore, after the virus enters the central nervous system, infected astrocytes secrete the tat protein. Tat protein disrupt the permeability of the blood–brain barrier throughing promoting apoptosis of endothelial cells and affecting the expression of tight junction proteins in the epithelium of the blood–brain barrier, which will help the virus to enter the central nervous system more easily [38], [39], [40]. HIV infects microglia, perivascular macrophages and astrocytes but not neurons directly via CD4 receptors and the mainly CCR5 co-receptor [41], [42].

Infected cells in the central nervous system can directly or indirectly attack neurons by releasing neurotoxic viral proteins, cytokines or neurotoxic substances that can affect neuronal function. The neurotoxic proteins tat and gp120 produced by infected cells can directly impair neuronal signals transmission and synaptic plasticity, affect neuronal autophagy and induce neuronal apoptosis [43], [44], [45], [46]. Neurotoxic proteins such as tat and gp120 activate uninfected astrocytes and microglia to damage neurons indirectly through promoting the release of associated inflammatory mediators [32]. HIV-infected astrocytes and microglia can also damage neurons by releasing neurotoxic agents. Activated microglia release NO, arachidonic acid, glutamate, and astrocytes release glutamate and oxygen radicals, all of which are neurotoxic. These neurotoxic agents can direct damage to neurons and also activate centrally resident immune cells, which stimulate a central inflammatory response impairing neuronal function indirectly.

2.3. Zika virus induces cognitive decline

Due to associated newborn and adult neurological disease, Zika virus represents a serious threat to global health. Zika virus is mainly transmitted by mosquito, but can also be transmitted from mother to child, via blood or sexual transmission [47]. Pregnant women are the largest victim group affected by the Zika virus, leading to the transition from mother to child and causes congenital microcephaly or other abnormal neurological disorders in the infants [48]. The earlier pregnant woman is exposed to Zika virus during pregnancy, the greater the probability of neurological abnormalities in the fetus [49]. Zika virus infection can cause associated neurological disorders such as congenital microcephaly, Guillain-Barré syndrome, meningitis, myelitis, radiculitis and acute disseminated encephalomyelitis [50], [51], so it is considered as a great threat to our neurocognition. Microcephaly is characterized by a head circumference that is three or more standard deviations below the mean compared to normal infants of the same sex and age, a small brain volume resulting in abnormal craniofacial proportions, and a small or absent cerebral gyrus [52], [53]. The victim children show abnormal brain development, mental retardation and even epilepsy, abnormal movement, speech and movement disorders [18], [54]. Zika virus can also affect the central nervous system in adults, impairing neurocognitive function. Adults infected with Zika virus can develop Green-Barre syndrome, which is an autoimmune peripheral neurological disease characterized by demyelinating lesions of peripheral nerves and nerve roots and inflammatory cell infiltration of small blood vessels [55], [56]. These patients may suffer from motor deficits, sensory deficits, reflex deficits and vegetative dysfunction [57].

It is demonstrated that Zika virus invades the central nervous system and infects neural progenitor cells in the subventricular zone of the forebrain and the subdentate gyrus of the hippocampus. This leads to apoptosis of infected progenitor cells, reduced neuronal production and abnormal migration of progenitor cells, resulting in abnormal brain development and cognitive impairment [58], [59], [60]. Zika virus can promote neuronal apoptosis and stem cell depletion by altering metabolic changes and inducing endoplasmic reticulum stress within neural stem cells [61], [62]. Zika virus can also infect microglia, oligodendrocytes and early astrocytes in the central nervous system. The microglial progenitor cells of the yolk sac are susceptible to Zika virus infection. After being infected by the virus, microglial progenitor cells carry the virus into the fetal brain, leading to other types of nerve cells being further infected by the virus [63]. Microglia infection also causes elevated expression of TNF-α, IL-6, IL-1β and inducible nitric oxide synthase in the central nervous system, inhibiting the differentiation and proliferation of neural progenitor cells [64]. Viral infection of oligodendrocytes reduces the synthesis of myelin and damages the structure of the axon, causing changes in the morphology of neurons and intracellular molecules and affecting the transmission of signals between neurons [65]. Moreover, infection of oligodendrocytes diminishes the nutritional support provided to neurons, thus affecting their function [66]. Astrocytes are also a target of Zika virus attack, with infected astrocytes disrupting neuronal synapses and the maintenance of homeostasis in the central nervous system [67]. Astrocytes can also engulf neural progenitor cells that have been infected by the virus which promote viral infection of surrounding normal cells. Virus-infected astrocytes are also an important source of many cytokines in the central nervous system [68].

3. Linkage between systemic and local inflammation and cognitive decline following infection

In addition to pathogens induced local inflammation, systemic inflammation is also an important trigger for the local inflammation within the brain. Microglia, as resident cells of the central nervous system (CNS), account for 10% of the total number of cells in the adult central nervous system [69]. Microglia play physiological roles in learning and memory by promoting learning-related synapse formation through brain-derived neurotrophic factor (BDNF) signaling [70]. The phagocytic activity of microglia is essential for the clearance of senescent cells and debris, preventing the toxic effects of amyloid-β [71]. Meanwhile, microglia can respond quickly to various CNS injuries including trauma, ischemia, and infection [72]. So microglia act as a critical immune homeostasis regulator in the central nervous system. The status of microglia determines the outcomes of the infection.

Within the brain, the communication between neurons and microglia are affected by many “off-signals” which mediate immune inhibition and “on-signals” which mediate immune activation. In the immune inhibitory resting status microglia are responsible for synaptic pruning which is necessary for precise neuronal circuitry during development and for synaptic plasticity in the adult brain. CD200 which expressed on neurons and CD200R which expressed on microglia are important off-signal. When microglia is activated by on-signals such as damaged neurons secreted ATP, microglia migrate to sites of inflammation and secrete proteins such as cytokines, chemokines and reactive oxygen species. These molecules can lead to synaptic plasticity and learning and memory deficits. The balance between the resting and the activated microglia plays a critical role in maintaining the homeostasis of the central nervous system.

Of notes, the “on-signals” is always activated following infection. Understanding how the “on-signals” is activated during infection is important for understanding how infection affects the local immune response which resulting in cognitive decline.

3.1. Following infection, systemic inflammation increases BBB permeability and leads to neuroinflammation

Increasing lines of evidence have shown that systemic inflammation can modulate neuroinflammation which contribute to neurodegeneration. The central nervous system (CNS) has once been considered to be an immune-privileged system. However, this viewpoint has changed recently as studies have shown that systemic inflammatory mediators can increase the permeability of the blood–brain-barrier (BBB), leading to the transmigration of activated macrophages and other immune cells across the BBB [73]. Clinical and experimental studies have demonstrated that peripheral immune activation following infection can activate immunological responses in the brain. For example oral infections have been associated with brain disorders, further supporting the view that the CNS is actively interacting with the peripheral immune system [74]. Injection of live Escherichia coli increases mRNA expression of IL-1β, TNF-α, IL-6 and COX-2 in the hippocampus and hypothalamus of mice within 4 h [75]. Systemic injection of LPS leads to the upregulation of pro-inflammatory cytokines and glial fibrillary acidic protein in the cortical regions. These data showed that systemic inflammation increases BBB permeability and cortical inflammation and glial activation can be triggered simultaneously and shortly following infection [76].

Mechanisms by which peripheral cytokines cross blood–brain-barrier are also investigated. Tight junction proteins play an important role in maintaining tight junction stability and BBB function. Data showed that cytokines such as TNF-α and IL-6 mediate destruction of tight junctions through decreasing the expression of inter-endothelial junction proteins in a dose- and time dependent manner [77]. In vitro experiment showed that prolonged exposure of TNF-α and IL-1b also lead to a reduction in the expression of occludin in human endothelial cells HUVECs [78]. However, the mechanisms by which systemic inflammation increases BBB permeability in detail remain to be determined.

3.2. Following infection, the homeostasis status of microglia determines the outcomes of neuroinflammation

Microglia, which derived from the primitive macrophages of the yolk sac, have the ability to self-renew, thus maintaining their number throughout life without any input from the bone marrow-derived precursor cells [79], [80]. As mentioned above, the activity of microglia is regulated by on-signals and off-signals. Unfortunately, uncontrolled activation of microglia lead to neuroinflammation. During infection, microglia act as a double-edged sword. On the one hand, microglia can sense ATP signals from injured neuron through the purinergic receptor P2Y12 and are then recruited around infected neurons to exert phagocytic activity. In addition, microglia can mediate antiviral immune response by inducing autophagy or by secreting cytokines such as interferon to activate antiviral T cell response. On the other hand, complement activation following infection may lead to excessive deposition of the complement components on the neuron, then microglia mediate presynaptic membrane damage in the hippocampus through complement receptor, resulting in long-term memory impairment and cognitive dysfunction in patients with encephalitis. Recently, how microglia are recruited around infected neurons and the interaction between microglia and neuron has become a hot topic. Tightly regulating the function of microglia to clear pathogens while maintains the immune homoestasis is the next research direction.

So far many pathways are involved in the cross-talk between microglia and neurons during infection. For example, P2Y12 receptors on the surface of microglia which recognize ATP, increased significantly in response to viral infections. Then microglia are recruited around the infected neurons by sensing ATP signals around the injured neurons. Physiologically, microglia accumulating around the olfactory bulb acting as a natural immune barrier plays an important role in limiting the spread of VSV in the CNS and preventing lethal encephalitis. Other data showed that the formation of the intrinsic microglia barrier is regulated by IFNAR signaling of neurons [81]. It is known that autophagy clears infection by capturing pathogens in the cell without causing cell death, which is beneficial for mature neurons. Microglia also restrict viral infection by inducing autophagy [82]. Besides cell–cell interaction, microglia produce considerable amounts of TNF-α, IL-1β, and IP-10 during infection. IP-10 possesses direct antiviral activity in neurons [83]. However, uncontrolled or dysregulated activation of microglia may cause pathogenic effects. For example, HIV-1-infected microglia release neurotoxins, cytokines and glutamate; activate NMDA receptors on neurons; cause calcium influx, inhibit neuronal autophagy; enhance apoptotic pathways; and ultimately lead to neuronal death [84]. SARS-CoV-2 activates microglial in the hippocampus promoting the expression of IL-1βand IL-6, which will inhibits neurogenesis, and we all know the hippocampus is responsible for learning, memory and executive function [85]. In addition, SARS-CoV-2 can activate microglia through activation of NLRP3 inflammasome, causing a sustained inflammatory response in the central nervous system, which will deteriorate cognition by impairing neuronal activity [86]. In viral encephalitis, Aβ produced by neurons increases the risk of dementia in patients. Microglia express C3aR, which recognizes C3 cleavage products. C3 and its cleavage products attract microglia to gather around the neurons to exert phagocytosis activity and to clear the presynaptic ends [87]. This explained how microglia-mediated synaptic loss causes memory impairment.

4. Critical pathways mediating neuroinflammation following infection

4.1. CCR5

CCR5, a seven-membrane G protein-coupled receptor (GPCR), is initially identified as a chemokine receptor expressed on immune cells [88]. Later, CCR5 is also found to be highly expressed in microglia and to a lesser extent in neurons and astrocytes [89] and is reported to act as a suppressor for synaptic plasticity and learning and memory. CCR5 knockout mice had enhanced long-term potentiation (LTP), which is believed to be an underlying cellular mechanism for learning and memory, both in the barrel cortex and hippocampus and demonstrated enhanced memory when tested 24 h or 2 weeks after contextual fear conditioning [90]. Consistently, CCR5 overexpression in excitatory neurons caused learning and memory deficits both in water maze and fear conditioning [91].

It is also well known that CCR5 is a co-receptor for HIV infection, and is involved in HIV-associated cognitive impairments. HIV binds to CCR5 via its gp120 V3 domain and activates this chemokine receptor. CCR5 may cause neurocognitive disorders via two different signaling pathways. The first pathway, which is an acute direct pathway, is that CCR5 signaling inhibits CREB, MAPK, and dual leucine zipper kinase (DLK), which play important roles in synaptic plasticity, subsequently leading to cognitive decline [90], [92]. CCR5 may also directly contribute to HIV mediated cognitive decline via promoting gp120 mediated neuronal apoptosis [93]. A chronic, indirect pathway activates microglia, causing neuroinflammation, as marked by increased release of reactive oxygen species, viral proteins, pro-inflammatory chemokines, and cytokines contributing to neuronal apoptosis which lead to inhibited neuronal excitability and plasticity, finally leading to HIV-associated neurocognitive disorders (HAND) [94]. N-methyl-D-aspartic acid receptor (NMDA), an ionotropic glutamate receptor, are critical for synaptic plasticity during learning and memory [95]. Abnormal glutamate metabolism or overactivation of NMDA signaling contribute to dendritic spine loss [96]. Study showed that CCR5 was involved in HIV gp120 mediated down-regulation of NMDA receptor(NR1) phosphorylation in cortical neurons [97]. Consistently, CCR5 antagonists block gp120 binding to CCR5, ameliorating these deficits.

4.2. CDK5

Cyclin-dependent kinase 5 (CDK5) is proline-directed serine/threonine kinases that belongs to the cyclin-dependent kinases family, and is the predominant CDK expressed in the adult brain [98]. CDK5 play important roles in neuronal/synaptic functions, including neuronal migration, neurite outgrowth, axonal guidance, and synaptic plasticity. Synaptic plasticity reflects modification of the efficacy or strength of synaptic transmission in response to neuronal activity and is integral to memory formation. There are multiple mechanisms regulating synaptic plasticity i.e. pre- and post-synaptic levels of modification [99]. At presynaptical level, CDK5 controls exocytosis, endocytosis, and Ca₂₊ influx. Dissociation of CDK5 induces Ca₂₊ influx into the pre-synaptic cytoplasm, which increases the channel opening and facilitates the release of neurotransmitters [100]. In addition, CDK5 impact various biological and cellular systems such as circadian clocks, DNA damage, cell cycle reentry, mitochondrial dysfunction etc. Beside its expression and function in the brain, CDK5 is expressed in immune cells such as neutrophils macrophages and T-cells and was shown to be involved in the regulation of inflammation [101], [102], [103]. Noncyclin proteins p35 and p39, which are the activators of CDK5, physically associates with CDK5 in brain and could activate CDK5 upon direct binding [104], [105]. As brain-derived neurotrophic factor (BDNF) can regulate CDK5 activity by enhancing p35 expression and by increasing CDK5 phosphorylation, BDNF is accepted as a critical regulator for CDK5 [106], [107].

However, following infection, abnormal CDK5 activation leads to neural damage through different ways, one of which focusing on the phosphorylation of tau protein. The hyperphosphorylation of tau has been associated with neurodegeneration via apoptosis [108]. In AD model, deletion of tau is protective for cognition [109]. In patients with HIV, calpain activity and the subsequent calpain-mediated generation of p25 from p35 were increased, leading to hyper activation of the CDK5 pathway [110]. p25 has an approximately 5- to 10-fold longer protein half-life compared to p35. Data showed that p25 promotes CDK5 hyperactivation and redirects CDK5 to a wider array of substrates under pathological contexts [111]. In an in vitro experiment, neuronal progenitor cells (NPCs) were infected with a viral vector expressing p35, and exposed to amyloid-β protein (Aβ1-42). These conditions resulted in impaired maturation and neurite outgrowth in vitro, and these effects were reversed by pharmacological or genetic inhibition of CDK5 [112]. However the mechanisms by which CDK5 is regulated during infection remain to be determined [113]. An explanation is excitotoxins released by HIV-infected microglia to trigger increased intracellular calcium influx, which in turn, could activate calpain cleavage of p35 into p25 and result in abnormal activation of CDK5 [114], [113]. Overexpression of p25 in neurons result in increased tau phosphorylation and elevated levels of Aβ peptide from the cleavage of APP, exhibit severe neuronal loss and reduced hippocampal LTP induction, lead to increased anxiety, and memory impairment [115]. Another report showed that HIV proteins could interfere with the transcriptional regulation of p35 and CDK5 [116]. CDK5 knockdown ameliorated the learning and memory deficits, decreased tau phosphorylation and reduced astrogliosis in HIV gp120Tg mice, indicating that gp120-CDK5-tau pathway play a pathogenic role in HIV associated neurodegenerative diseases [117]. It is also noteworthy that, a report by R. Dixon Dorand showed that INF-gamma induces p35, which results in enhanced CDK5 activity. These data explained how systemic or local inflammation exacerbate cognition in vivo [118], [119].

Other reports showed that CDK5 can bind to and phosphorylate NMDA receptor then induces the apoptosis of neurons [120]. NMDA receptor R2B subunit plays an important role in synaptic plasticity and learning and memory functions [121]. CDK5 may also induces cognitive deficits through promoting the degradation of NR2B [122].

Besides the regulators such as p25, CDK5 can also be modulated by a variety of post-translational modifications. Reports showed that CDK5 phosphorylation at Tyr 15 is stimulatory while phosphorylation at Tr 14 is inhibitory [123]. Whether pathogens trigger the pathogenic roles of CDK5 via phosphorylation modification remain to be determined.

4.3. Dysregulated autophagy and cognitive decline

It is known that autophagy regulates and balances defense response to avoid excessive inflammation. During infection, tightly controlled autophagy of the infected cells including infected neurons contribute both to the clearance of the infected pathogens and to the prevention of excessive inflammatory response. Generally, autophagy clears cytosolic protein aggregates, intracellular microbes and ingested extracellular debris, such as danger associated molecular patterns (DAMPs) [124]. Based on the difference of cargos, autophagy can be defined into different subtypes. Xenophagy means direct elimination of intracellular pathogens. Mitophagy means the removal of mitochondria. Lysophagy means the removal of damaged lysosomes, etc. Recently, much research has been focused on xenophagy, by which the intracellular bacteria, parasites, and viruses were processed to maintain or restore homeostasis. The antiviral activity mediated by autophagy encompasses two mechanisms. Firstly, intracellular viral particles or eosynthesized viral components is directly degraded (xenophagy). This effects particularly useful for long-lived cells such as neurons. Secondly, xenophagy induces the innate and adaptive immune systems to produce antiviral immunity, i.e. contributing to class II presentation of viral antigens by microglia or astrocytes during CNS infection [125], [126]. Data showed that enhancing autophagy by inoculating mice with a Beclin-1 peptide decreases viral burden and improves survival during chikungunya virus and West Nile virus infections [127]. Unfortunately, viruses have evolved mechanisms to subvert autophagy. Successful intracellular bacteria almost invariably developed specific defenses against autophagy, which underscores antimicrobial and immunological significance of autophagy [128]. Two major mediators of HIV-induced neurotoxicity, tumor necrosis factor-alpha and glutamate, had similar autophagy reducing effects in neurons [84]. The virulence factors and their hijack targets to disturb autophagy were summarized by Matthew D. Keller [128].

When xenophagy fails, inflammatory responses become exaggerated and, this comes at a cost causing tissue damage and inflammatory pathology. The effects of autophagy homeostasis on the infection induced cognitive decline remain to be determined. Although there are reports showed that the induction of autophagy in neurons through rapamycin treatment conferred significant protection to neurons in SIV-infected brains [84], the clinical application of this kind of regulators must await a more in-depth understanding of the detail process of autophagy. Some infectious agents may take advantage of autophagy by replicating within autophagic vacuoles [129].

4.4. Complement and others

As an important arm of both innate and humoral immunity, the complement system play critical roles in clearing pathogens and maintaining immune homeostasis. Of note, the complement cascade also mediates synaptic pruning by microglia during early postnatal development. During infection, the complement system can be initiated by neurotoxic proteins from pathogens and damaged cells. The complement components such as C1q, C3a, C5a, which could promote vasodilation and stimulate innate and cellular immune responses, may be made locally by damaged neurons, or may come from plasma through a disrupted BBB. However, uncontrolled complement activation lead to autoimmune damage. Many reports showed that complement contribute to infection-induced neuroinflammation and cognitive decline. Michael J Vasek et al. reported that over 50% of patients who survive neuroinvasive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae. In a murine WNV neuroinvasive disease model, viral infection of adult hippocampal neurons induces complement-mediated elimination of presynaptic terminals. Their study suggests that complement C3 and C3aR which expressed on neurons and microglia mediate presynaptic terminal loss in the hippocampi of mice that exhibit spatial learning defects during recovery from West Nile neuroinvasive disease. This study suggested a complement- and microglial-dependent synapse elimination [130], [87].

There are many other signaling pathways controlling the homeostasis of microglia during infection. Data have shown that the interaction of CD200R, an off-signal expressed on microglia, with the CD200 ligand expressed on neurons leads to downstream inhibition of pro-inflammatory pathways, maintaining microglia in a resting state [131], [132], [133].

As a known regulator of immune homeostasis, CD200R evolved as a strategy to prevent autoimmunity and prolonged inflammation in the CNS. It is also noteworthy that although at the ultrastructural level, a great enrichment of CD200 has been reported in pre-synaptic and post-synaptic elements of excitatory synapses [134], due to the inability of CD200 to transduce intracellular signals, all outcomes derived from the CD200-CD200R engagement will be the result of CD200R activation. Or in other words, CD200/CD200R mediated neuronal-microglial interactions impart a unidirectional immune-inhibitory signal that suppresses microglia activation and contribute to the immune-privileged status of the CNS [135].

Data showed that CD200R also expressed on other myeloid cell. CD200/CD200R signaling functions as a critical regulator of the immune response both in the peripheral and in the central nervous system. In an stroke model, Ritzel et al. reported that CD200-CD200R1 interactions are important for downregulating neuroinflammatory responses via both attenuation of microglia proliferation and inhibition of monocyte and T cell entry into the ischemic brain. And CD200/CD200R mediated attenuation of excessive immune response is critical for preventing spontaneous lung infection [136]. Other reports showed that CD200 deficiency enhances pathological T cell responses during influenza infection [137]. In the presence of LPS, microglia from CD200-deficient mice are highly activated, as shown by increased TNF-α, IL-1β and iNOS [138]. Mice lacking CD200 display an enhanced sensitivity to influenza infection, leading to delayed resolution of inflammation and death [139]. These findings implicate the CD200-CD200R1 immunoregulatory pathway as a novel and powerful therapeutic target during infection.

5. Summary

Biosafety infections may induce cognitive decline though different ways. Although pathogens could directly induce cognitive decline via increasing levels of oxidative stress, depositing of misfolded protein aggregates, causing deficient of autophagic processes, neuronal death and synaptopathies, the activation of the defense immune response to eradicate the pathogen also significantly contribute to neuronal damage [140]. In addition to the local inflammation within the CNS, systemic immune activation is another feature contributing to neuroinflammation. Peripheral cytokines have the potential to reach the brain parenchyma, initiate a local immune response, and subsequently impair cognitive function. In this review, we mainly focus on the mechanisms of systemic and local inflammation mediated cognitive decline, especially highlighting the communications between microglia and neurons in both physiological and pathological conditions. microglia and several molecular pathways triggered by pathogens or immune response.

So far, although it is known that, following infection, moderately regulates the activity such as the phagocytosis and autophagy activity of microglia can reduce the risk of dementia, the strategies need further research. Target intervening of the critical pathways such as the CCR5, CDK5, CD200/CD200R, or complement pathway may hold therapeutic potential for the prevention of infection induced cognitive decline.