key: cord-324619-y7gilopu
authors: Alam, S.B.; Willows, Steven; Kulka, Marianna; Sandhu, Jagdeep K.
title: Severe acute respiratory syndrome coronavirus‐2 may be an underappreciated pathogen of the central nervous system
date: 2020-07-15
journal: Eur J Neurol
DOI: 10.1111/ene.14442
sha: 
doc_id: 324619
cord_uid: y7gilopu

Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) causes a highly contagious respiratory disease referred to as COVID‐19. However, emerging evidence indicates that a small, but a growing number of COVID‐19 patients also manifest neurological symptoms, suggesting that SARS‐CoV‐2 may infect the nervous system under some circumstances. SARS‐CoV‐2 primarily enters the body through the epithelial lining of the respiratory and gastrointestinal tracts, but under certain conditions this pleiotropic virus may also infect peripheral nerves and gain entry into the central nervous system (CNS). The brain is shielded by various anatomical and physiological barriers, most notably the blood‐brain barrier (BBB) which functions to prevent harmful substances, including pathogens and pro‐inflammatory mediators, from entering the brain. The BBB is composed of highly specialized endothelial cells, pericytes, mast cells and astrocytes that form the neurovascular unit, which regulates BBB permeability and maintains the integrity of the CNS. In this review, we briefly discuss potential routes of viral entry and the possible mechanisms utilized by SARS‐CoV‐2 to penetrate the CNS, either by disrupting the BBB or infecting the peripheral nerves and using the neuronal network to initiate neuroinflammation. Furthermore, we speculate on the long‐term effects of SARS‐CoV‐2 infection on the brain and in the progression of neurodegenerative diseases known to be associated with other human coronaviruses. Although the mechanisms of SARS‐CoV‐2 entry into the CNS and neurovirulence are currently unknown, the potential pathways described here might pave the way for future research in this area and enable the development of better therapeutic strategies.

On December 27 th , 2019 the Chinese Center for Disease Control and Prevention announced that it had detected a cluster of patients in Wuhan, China who had developed severe pneumonia of unknown etiology, later termed COVID-19 (Coronavirus disease of 2019) (1) (2) (3) . These patients were described as presenting with mainly fever, with a few patients having Accepted Article difficulty in breathing and on January 8 th , 2020 the causative agent of COVID-19 was identified as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (4). In the subsequent six months, SARS-CoV-2 has become a worldwide pandemic, infecting over eleven million people and killing more than 540,000 patients worldwide (https://www.jhu.edu/; https://coronavirus.jhu.edu/), while also crippling the world economy. Although COVID-19 was first described as a respiratory disease, new data shows that SARS-CoV-2 can infect almost every organ, resulting in an ever-increasing list of symptoms. In particular, neurological symptoms and disturbances in the central nervous system (CNS) are common in many COVID-19 patients, and may be a predictor of disease severity. In this review, we examine some of the most recent data of COVID-19-associated neurological disease and the possibility that SARS-CoV-2 may be infecting the CNS. In particular, we examine the possible mechanisms of viral entry through the blood-brain barrier (BBB) and the peripheral nerves and we discuss the possible long-term consequences of viral infection in the brain by surveying data from closely related, neurotropic viruses. Since viral infection of the CNS often has long-term neurological implications for patients, the possibility that these types of infections could lead to neurodegenerative diseases is discussed.

Even in the early months of the COVID-19 pandemic, physicians observed that a significant subset of patients positive for SARS-CoV-2 presented with neurological complications, sometimes accompanied with respiratory distress. In February 2020, Li et al. suggested that since SARS-CoV-2 shared significant similarities to severe acute respiratory syndrome coronavirus (SARS-CoV), it was entirely possible that SARS-CoV-2 could similarly penetrate the brain and CNS of infected patients through synapses in the medullary cardiorespiratory center and thereby cause respiratory failure (5) . Quickly thereafter, several studies of severely ill COVID-19 patients in Wuhan described neurological symptoms including autopsy observations of deceased patients which showed brain tissue edema and partial neuronal degeneration (6) . In a retrospective study of hospitalized patients with laboratory confirmed SARS-CoV-2 infection in Wuhan, China, 36.4% of patients exhibited neurological symptoms (7), such as dizziness (16.8%) and headache (13.2%), while neurological symptoms were more common in severe versus non-severe patients (45.5% vs 30.3%). Several symptoms Accepted Article were more specifically associated with severe disease, such as impaired consciousness (14.8% in severe vs 2.4% in non-severe), acute cerebrovascular disease (5.7% vs 0.8%), and skeletal muscle injury (19.3% vs 4.8%). Other studies also found incidences of headache, dizziness and confusion in 5-9% of hospitalized patients (8) and a single study from Wuhan, China reported similar rates (~5%) of acute cerebrovascular disease in severely affected COVID-19 patients (9) . A retrospective analysis of deceased patients in China found a high rate of disorders of consciousness upon admission to the hospital, suggesting neurological complications were an indicator of poor prognosis (10) . In the past -six months, we have learned that the loss of taste and smell is an early sign of SARS-CoV-2 infection, affecting approximately 5% of Chinese patients (7), 30-40% of European patients (11) (12) (13) , and is most prevalent in young women (12, 13) . This observation is especially significant since it has been suggested that human coronaviruses, such as SARS-CoV (in mice) and HCoV-OC43 (in mice and humans) enter the brain through the olfactory bulb (14) . A recent cross-sectional study reported that the cumulative incidence of COVID-19 was higher in patients with active epilepsy as compared to control subjects without epilepsy (15) . Another study showed that plasma biomarkers of CNS injury, namely neurofilament light chain protein (NfL), a marker for neuronal injury and glial fibrillary acidic protein (GFAP), a marker for astrocytic injury were significantly elevated in patients with moderate and severe COVID-19 (16). Histopathological examination of brain specimens from a cohort of 18 COVID-19 patients showed acute hypoxic injury in the cerebrum and cerebellum and loss of neurons in the cerebral cortex, hippocampus and cerebellar purkinje cell layer (17).

A retrospective study from China found that COVID-19 patients over 60 years old and with neurologic comorbidities were at a higher risk of developing neurologic impairments such as impaired consciousness and cerebrovascular accidents (18).

SARS-CoV-2 belongs to the betacoronavirus genus in the coronaviridae family (19). With the exception of HCoV-229E and HCoV-NL63 (Alphacoronaviruses), human coronaviruses (HCoVs) belong to the betacoronavirus genus. All human coronaviruses have animal origins (20) and cross-species transmission appears to happen when low affinity binding occurs in receptors closely related between host species. Two strains of SARS-CoV isolated from palm civets, for example, had high affinity for civet receptor angiotensin converting enzyme II (ACE2) and high infectivity in civet cells but these same two strains of SARS-CoV had low affinity for human ACE2 and therefore low infectivity in human cells (21). Similar to SARS-CoV,

This article is protected by copyright. All rights reserved SARS-CoV-2 also binds to human ACE2 with high affinity and is likely the principal entry route into human respiratory cells (22, 23). Similar to SARS-CoV, SARS-CoV-2 also requires the transmembrane serine protease 2 (TMPRSS2) for spike protein priming and entry into the host cell (22), although it might vary depending on the cell type (24, 25). Therefore, cells that express ACE2 and TMPRSS2, such as the glia and neurons, would be plausible targets for SARS-CoV-2 infection (26) . infections are associated with headache, dizziness, axonopathic polyneuropathy, myopathy, ischemic stroke, ataxia, febrile seizures, convulsions, loss of consciousness and encephalomyelitis encephalitis (14) . In fact, some of these viruses have been found in the CNS of their hosts (31) (32) (33) (34) (35) . SARS-CoV has been isolated and cultured from the brain of a severe acute respiratory syndrome (SARS) infected patient, providing evidence that SARS-CoV is able to infect the human brain (32) . HCoV-OC43 has been associated with fatal encephalitis in immunocompromised pediatric patients, demonstrating direct evidence for the presence of viral proteins and RNA in neuronal cells in the autopsied brain tissue (33, 35) . A first case of SARS-CoV-2 meningitis/encephalitis has been reported recently, where RNA has been detected in the cerebrospinal fluid (CSF) (34) , suggesting that SARS-CoV-2 can invade the CNS. Similar to these neurotropic HCoVs, SARS-CoV-2 infection in the lungs of some COVID-19 patients may also lead to entry into the CNS and this could occur via two main pathways: i) infection of peripheral nerves and retrograde axonal transport; and/or ii) hematogenous spread and infection of the cells of the blood-brain barrier.

The peripheral organs are highly innervated with neurons that link the peripheral nervous system (PNS) with the CNS and neuroinvasive viruses have evolved several strategies to access the CNS via the transneural route (19, 31, 36) . For example, viruses can manipulate the neuronal cytoskeletal machinery of the microtubules and Accepted Article molecular motors, such as dynein and kinesin to traffic virions via a retrograde and anterograde transport route, respectively from the PNS into the CNS (36) . After replication in the neuronal cell body, fully assembled viral particles are released into the synaptic cleft and infection is spread to presynaptic neurons. As will be discussed in more detail below, most RNA viruses, including a number of coronaviruses have been shown to enter the CNS by utilizing the transneural pathway (19, 31) . Given the fact that SARS-CoV-2 is an RNA virus and has substantial similarity with other coronaviruses (that belong to the same family of viruses), we hypothesize that it might deploy similar entry routes to access the CNS (Figure 1 ). Viruses can also spread to the spinal cord from the trigeminal nuclei via the reticular formation and the reticulo-spinal tract (45) and this trans-synaptic transfer has been reported for avian bronchitis virus (a gammacoronavirus) (46, 47). Experimental studies using transgenic mice revealed that both SARS-CoV and MERS-CoV, when inoculated intranasally, entered the brain, possibly via the olfactory nerves, and thereafter rapidly spread to some specific brain areas including thalamus and brainstem (29, 48) . Therefore, if viral replication in the nose is Accepted Article sufficiently high, it is possible that these high viral titres could infiltrate the olfactory nerve. Nasal swabs of symptomatic and asymptomatic COVID-19 patients have higher viral loads than throat swabs (3, 49) , suggesting these cells might be the loci of viral replication and possible reservoirs for dissemination within the nasal cavity to the olfactory nerve.

the lungs and spreads to the brain via the retrograde axonal transport in the vagus nerve (46, 50) . The vagus nerve travels through the neck and thorax to the stomach and it connects the lung to the gut and brain, also referred to as lung-gut-brain axis (51) . Since the lungs represent a major reservoir of SARS-CoV-2 infection, at least in the early stages of COVID-19 disease, it is possible that SARS-CoV-2 could use the vagus nerve to enter the CNS and travel throughout the lung-gut-brain axis, potentially interfering with all of these systems at different time-points during infection. This may explain why some patients experience a combination of gastrointestinal, neurologic and lung symptoms throughout the course of infection (52) .

The gut is a highly innervated organ with a complex gut microbiome and this complex network biochemically interacts with the host CNS, also known as the gut-brain axis. In fact the gut has often been referred to as a neurologic organ since it is innervated by five different classes of neurons: intrinsic enteric neurons, vagal afferents, spinal afferents, parasympathetic efferents and sympathetic efferents (53) . If SARS-CoV-2 gains access to this highly complex innervated network, it is possible that it could use this network to penetrate the CNS (54). 

This article is protected by copyright. All rights reserved neuroinflammation. The fact that many of these cytokines can promote vascular permeability and leakage resulting in BBB dysfunction, suggests that infection in the gut could be another plausible route by which SARS-CoV-2 could penetrate the brain. into the brain via retrograde transport (61) . PHEV binds to NCAM expressed on the surface of medullary neurons to enter into the CNS. Since, SARS-CoV-2 belongs to the same genus as PHEV (betacoronavirus), it is possible that it might also deploy neuronal NCAM to enter the CNS. Additionally, previous studies have shown that ACE2 is present on skeletal muscles (62) .

Hence, SARS-CoV-2 might bind to ACE2 receptors present on skeletal muscles and enter the CNS via retrograde transport. In support of this argument, it has been shown that 19.3% of patients with severe COVID-19 related neurological manifestations had skeletal muscle injury (7). The prevalence of myalgia between 11-50% and muscle weakness related to COVID-19 has been reported in several studies (63) (64) (65) . Acute myositis has also been recognized as a manifestation of COVID-19 on MRI scans (66) and in at least one specific case, an afebrile COVID-19 patient was hospitalized and did not present any upper and lower airway symptoms, but had elevated creatine kinase and C-reactive protein levels, suggestive of muscle

This article is protected by copyright. All rights reserved inflammation (66) . During the 2015 MERS-CoV outbreak in the Republic of Korea, four patients in a cohort of 23 (17.4%) experienced neuropathies and limb weakness, neurological complications that lasted months after initial infection (67) . It is possible that COVID-19 patients that have experienced SARS-CoV-2 infection of the CNS via the neuromuscular junction could experience similar complications and long-term follow-up of these patients should be prioritized.

Normally, viral entry from the blood into the CNS is restricted by the blood-brain barrier (BBB), which forms a structural and functional barrier between the peripheral circulation and the CNS. The BBB is comprised of highly specialized cerebrovascular endothelial cells, pericytes, mast cells and astrocytes that function together as a neurovascular unit to maintain homeostasis (68, 69) . The total length of brain capillaries in humans is approximately 600 km with a surface of 15-25 m 2 , providing a large area for viral invasion (70) . The neurovascular unit serves as the gate-keeper of the CNS that protects the brain by regulating the cerebral blood flow and limiting the access of pathogens, 

This article is protected by copyright. All rights reserved interleukins (75) . The cytokine storm associated with SARS-CoV-2 infection results in increased secretion of pro-inflammatory cytokines and chemokines such as IL-6, TNF-α, MIP1-alpha, IP-10 and G-CSF as well as C-reactive protein and ferritin (64) . These cytokines and chemokines can bind to specific receptors on the cerebral microvascular endothelium leading to BBB breakdown, neuroinflammation and encephalitis. The loss of BBB integrity could loosen the TJs between the endothelial cells paving the way for paracellular traversal of SARS-CoV-2 into the CNS (Figure 2a) . A recent study on Japanese encephalitis virus (JEV, an RNA virus) suggests that paracellular mode of trafficking could be one of the potential routes of entry into the CNS (76) . JEV-infected mast cells release chymase, a vasoactive protease, which cleaves TJ proteins, including zona occludens-1 and 2, claudin-5 and occludin, breaking down the BBB and facilitating entry of JEV into the CNS.

Some neurotrophic viruses, such as JEV and WNV can enter into the CNS via the bloodstream in a process known as viremia (77) . 

In the "Trojan horse" strategy of neuroinvasion, the virus hides inside innate immune cells, HIV infects CD4-positive T-cells and utilizes chemokine CCR5 as a co-receptor to enter the CNS (85, 86) . Additionally, HIV also infects CD16-positive monocytes to travel across the BBB and infect brain microglia leading to chronic inflammation and eventually neuronal damage and dementia (36) . Human cytomegalovirus (HCMV) (87, 88) , enteroviruses including poliovirus (89) and flaviviruses (90) have also been shown to infect different types of leukocytes and to use them as a reservoir for hematogenous dissemination toward the CNS. It has been shown that ACE2 receptor is expressed on hematopoietic cells, including monocytes and lymphocytes.

T-cells via dipeptidyl peptidase 4 (91, 92) . It is possible that SARS-CoV-2 could infect monocytes and lymphocytes and traffic across the BBB and further infect neural cells. More recently CD147, also known as Basigin and EMMPRIN (Extracellular Matrix Metalloproteinase-Inducer) has been implicated as an alternative entry receptor for SARS-CoV-2, which is expressed on activated lymphoid, myeloid, epithelial and neuronal cells in the CNS (93, 94) . 

long-term neurologic effects of COVID-19? It is still too early to reliably predict the possible longterm health effects of SARS-CoV-2 infection but some general predictions are possible. Since there is substantial population variability in symptoms associated with acute SARS-CoV-2 infection, the long-term consequences of COVID-19 will also be variable, likely depending on sex and age (at the time of infection) of the patients. However, since other human coronavirus infections cause autoimmune and neurodegenerative diseases in their hosts, it is possible that Accepted Article these may also occur after SARS-CoV-2 infection. For instance, HCoV-OC43 and HCoV-229E antigens and RNA have been detected in the CSF and brain tissues of multiple sclerosis patients, where viral RNA persists in the absence of infectious virus (31, 105) . Another study showed that antibodies against HCoV-OC43 and HCoV-229E were found in the CSF of Parkinson's disease (PD) patients (106) . Patients infected with other neurotropic viruses, including WNV, JEV, HIV, H5N1 and IV develop Parkinsonian symptoms, including tremor, rigidity, and bradykinesia and infection with these viruses may increase the risk of developing PD (107) . Therefore, there is a possibility that the long-term presence of viral components in the brain of COVID-19 patients may induce chronic innate and adaptive immune responses that eventually lead to autoimmune and neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis in susceptible individuals.

The pathological hallmarks of many chronic neurodegenerative diseases are selective, such as progressive loss of neurons, accumulation of misfolded/aggregated proteins like amyloid-beta and alpha-synuclein as well as neuroinflammation (108) . As discussed above, COVID-19 patients present with olfactory and gastrointestinal issues and it is noteworthy that idiopathic olfactory dysfunction and vagal dysfunction are both early and common symptoms of preclinical PD and precede several years before the onset of classical motor dysfunction (109) .

With regards to PD etiology, Braak et al. had hypothesized that PD progresses through the nervous system in different stages (110) , which was later revised as the 'dual-hit' hypothesis by Hawkes et al. (111) . According to the 'dual-hit' hypothesis, a neurotropic viral pathogen likely enters into the brain through the olfactory pathway or the enteric nervous system and leads to misfolding and aggregation of alpha-synuclein protein and its translocation to the midbrain by 'prion-like' propagation throughout the brain as the disease progresses. In an earlier study Barnett et al. had showed that MHV entered the brain through the olfactory system and infected dopaminergic neurons in the substantia nigra and ventral tegmental area, respectively (112) .

Interestingly, MHV produced a widespread infection of the A10 group of neurons. It also infected neurons of the A8 and A9 groups, suggesting that MHV can damage the nigrostriatal and mesolimbic dopamine pathway. A growing body of literature has now revealed that majority of the proteins involved in neurodegenerative diseases are transported in exosomes (113) . Therefore, it is possible that exosomes play an important role in the transport of misfolded alpha-synuclein across the BBB into the brain parenchyma where it acts as 'seeds' in the recipient neural cells, spreading throughout the brain by a 'prion-like' mechanism. Chronic neurodegenerative diseases develop over decades with distinct preclinical, prodromal and clinical phases and the long-term impacts of SARS-CoV-2 on younger patients is not known but

This article is protected by copyright. All rights reserved could be a serious concern. If SARS-CoV-2 alters the long-term impacts on the CNS as described, they may manifest over years or decades. As recovered COVID-19 patients age, there might be an upsurge in the number of neurodegenerative diseases. Therefore, we propose that patients who have recovered from the acute phase of the SARS-CoV-2 infection, should be continuously monitored throughout their lives for the development of neurological symptoms associated with neurodegenerative disease.

At this time there are no therapeutics or vaccines approved by the US Food and Drug Administration (FDA) to specifically cure, treat or prevent COVID-19. However, the FDA continues to issue emergency approvals for "off-label" drugs to treat severe COVID-19 patients.

These drugs include antiviral drugs (remdesivir, chloroquine and hydroxychloroquine) and immunomodulators (tocilizumab, canakinumab and Anakinara), and some of them may contribute to neurological dysfunction. For example, chloroquine and hydroxychloroquine, which were commonly used earlier in the pandemic, could potentially increase the likelihood of neurological disorders, especially in the elderly (114) . The use of hydroxychloroquine has been associated with neuropsychiatric manifestations including irritability, nervousness and psychosis, possibly by its ability to cross the BBB (115) . Corticosteroids, another common group of medications used to treat severe cases of COVID-19, have also been associated with psychiatric symptoms, especially when administered at high doses (116) . The use of immunomodulators, such as tocilizumab (monoclonal antibody to IL-6 receptor), canakinumab (monoclonal antibody to IL-1β) and Anakinara (IL-1 receptor antagonist) are in clinical trials to dampen cytokine responses in severely ill COVID-19 patients, however they have poor BBB penetration into the CNS (117) . The use tocilizumab has been associated with multifocal cerebral thrombotic microangiopathy and adverse neurological effects on the CNS (118).

Finally, mechanical ventilation was, and continues to be, the principal medical intervention used to treat severe COVID-19 patients. However, some recent studies are raising the possibility that the use of mechanical ventilation can contribute to neurological injury, which can fuel further lung damage (119).

The current pandemic has spread globally to every country, infected millions of people and remains a major public health concern. While governments around the world are using Accepted Article various measures, such as lockdowns, quarantine and contact tracing to control the spread of infection, it is worth noting that these approaches might significantly impact patients with chronic neurologic disorders in unintended ways. For example, the COVID-19 quarantine in Italy created uncertainty and confusion about the availability of clinical services and continuity of care among PD patients (120) . Negative effects on mental health have been observed in those whose daily life was disrupted by the various public health measures (121) . Many drugs used to treat people with chronic neurological diseases are being repurposed to fight COVID-19 (122) (123) (124) , potentially leading to shortages and contributing to extra stress and worsening of disease symptoms.

Although we are rapidly learning about SARS-CoV-2 and its methods of infection, there is still much to learn. In this review, we have extrapolated information from other neurotropic viruses to make some predictions and it is clear that SARS-CoV-2 has the potential to infect the CNS and cause long-term neurologic damage in COVID-19 patients. The next few years will be critical if we are to determine the long-term effects of this pandemic on the neurological health of this population. We urge governments to create a framework and a national registry of patients who have been infected by SARS-CoV-2. Patients, particularly those with neurological symptoms, must be tracked regularly and consistently at ongoing time points over their life time using advanced neuroimaging and biochemical analysis of biomarkers to map the degenerative process. To this end, the Spanish Neurological Society has implemented a registry of neurological manifestations in patients with confirmed COVID-19. Román and colleagues have emphasized the need of COVID-19 international neurological databanks to report all cases of new-onset, acute, delayed, and any long-latency neurological disorders associated with SARS-CoV-2 infection during the COVID-19 pandemic (125). The development of a regional, national or international registry will not only provide a database but will also help develop strategies to better combat COVID-19-mediated neurological manifestations. In addition, a systematic research approach in this area will allow better understanding of the neurological impact of SARS-CoV-2 infection on different groups of the population, its impact on the CNS and COVID-19-associated long-term neurological consequences.

A Novel Coronavirus from Patients with Pneumonia in China

A new coronavirus associated with human respiratory disease in China

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Central nervous system manifestations of COVID-19: A systematic review

Acute Cerebrovascular Disease Following COVID-19: A Single Center

Clinical and immunological features of severe and moderate coronavirus disease 2019

Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms

Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study

Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? Viruses 12

Incidence and case fatality rate of COVID-19 in This article is protected by copyright. All rights reserved SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

The scRNA-seq expression profiling of the receptor ACE2 and the cellular protease TMPRSS2 reveals human organs susceptible to COVID-19 infection

Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice

Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4

Neurotropism of human coronavirus 229E

Neuroinvasion by human respiratory coronaviruses

Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis

Fatal encephalitis associated with coronavirus OC43 in an immunocompromised child

A first case of meningitis/encephalitis associated with SARS-Coronavirus-2

Human Coronavirus OC43 Associated with Fatal Encephalitis

Keeping it in check: chronic viral infection and antiviral immunity in the brain

Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

In vitro demonstration of neural transmission of avian influenza A virus

Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders

Digestive system is a potential route of COVID-19: an analysis of single-cell coexpression pattern of key proteins in viral entry process

The gut as a neurological organ

Can the enteric nervous system be an alternative entrance door in SARS-CoV2 neuroinvasion?

Review article: gastrointestinal features in COVID-19 and the possibility of faecal transmission

Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus

Impact of TGEV infection on the pig small intestine

Virus infections in the nervous system

Modulation of the immune response in the nervous system by rabies virus

Accepted Article This article is protected by copyright. All rights reserved 60

Human poliovirus receptor gene expression and poliovirus tissue tropism in transgenic mice

Poliovirus trafficking toward central nervous system via human poliovirus receptor-dependent and -independent pathway

Reninangiotensin system: an old player with novel functions in skeletal muscle

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Myositis as a manifestation of SARS-CoV-2

Neurological Complications during Treatment of Middle East Respiratory Syndrome

Development and Cell Biology of the Blood-Brain Barrier

Cellular elements of the blood-brain barrier

Structural and functional aspects of the blood-brain barrier

Illuminating viral infections in the nervous system

The blood-brain barrier

Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier

Mechanism of West Nile virus neuroinvasion: a critical appraisal

The blood brain barrier and the role of cytokines in neuropsychiatry

Japanese encephalitis virus and its mechanisms of neuroinvasion

Molecular pathogenesis of neurotropic viral infections

Structure and function of the blood-brain barrier

Zika virus crosses an in vitro human blood brain barrier model

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

West Nile virus infection modulates human brain microvascular endothelial cells tight junction proteins and cell adhesion molecules: Transmigration across the in vitro blood-brain barrier

Icam-1 participates in the entry of west nile virus into the central nervous system

West Nile virus: crossing the blood-brain barrier

Monocyte/macrophage traffic in HIV and SIV encephalitis

HIV-1 target cells in the CNS

Accepted Article This article is protected by copyright. All rights reserved 86

Identification of a major co-receptor for primary isolates of HIV-1

Human cytomegalovirus (HCMV) infection of endothelial cells promotes naive monocyte extravasation and transfer of productive virus to enhance hematogenous dissemination of HCMV

Human cytomegalovirus induction of a unique signalsome during viral entry into monocytes mediates distinct functional changes: a strategy for viral dissemination

Enterovirus infections of the central nervous system

Flaviviruses are neurotropic, but how do they invade the CNS?

Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells

Middle East Respiratory Syndrome Coronavirus Efficiently Infects Human Primary T Lymphocytes and Activates the Extrinsic and Intrinsic Apoptosis Pathways

SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

CD147 immunoglobulin superfamily receptor function and role in pathology

The biology, function, and biomedical applications of exosomes

Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells

Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells

Neurotropic virus infections as the cause of immediate and delayed neuropathology

Interferon-inducible effector mechanisms in cell-autonomous immunity

COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features

Pivotal Role of Receptor-Interacting Protein Kinase 1 and Mixed Lineage Kinase Domain-Like in Neuronal Cell Death Induced by the Human Neuroinvasive Coronavirus OC43

Microglia in human immunodeficiency virus-associated neurodegeneration

Detection of coronavirus RNA and antigen in multiple sclerosis brain

Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson's disease

Viral parkinsonism

Pathology of Neurodegenerative Diseases

Preclinical biomarkers of Parkinson disease

Staging of brain pathology related to sporadic Parkinson's disease

Parkinson's disease: a dual-hit hypothesis

The olfactory nerve and not the trigeminal nerve is the major site of CNS entry for mouse hepatitis virus

Exosomes in the Pathology of Neurodegenerative Diseases

Smooth or Risky Revisit of an Old Malaria Drug for COVID-19?

Psychomotor Agitation Following Treatment with Hydroxychloroquine

Psychiatric complications of treatment with corticosteroids: review with case report

Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques

Tocilizumab-associated multifocal cerebral thrombotic microangiopathy

The lung and the brain: a dangerous cross-talk

Self-reported needs of patients with Parkinson's disease during COVID-19 emergency in Italy

The immediate mental health impacts of the COVID-19 pandemic among people with or without quarantine managements

We thank the National Research Council Canada for intramural funding.

This article is protected by copyright. All rights reserved

This article is protected by copyright. All rights reserved

This article is protected by copyright. All rights reserved