Next-Generation Sequencing and Proteomics of Cerebrospinal Fluid From COVID-19 Patients With Neurological Manifestations.

The SARS-CoV-2 and its variants are still hitting the world. Ever since the outbreak, neurological involvements as headache, ageusia, and anosmia in COVID-19 patients have been emphasized and reported. But the pathogenesis of these new-onset neurological manifestations in COVID-19 patients is still obscure and controversial. As difficulty always lay in the diagnosis of neurological infection, current reports to validate the presence of SARS-CoV-2 in cerebrospinal fluid (CSF) almost relied on the basic methods and warranted improvement. Here we reported a case series of 8 patients with prominent new-onset neurological manifestations, who were screened out from a patch of 304 COVID-19 confirmed patients. Next-generation sequencing (NGS) and proteomics were conducted in the simultaneously obtained CSF and serum samples of the selected patients, with three non-COVID-19 patients with matched demographic features used as the controls for proteomic analysis. SARS-CoV-2 RNA was detected in the CSF of four COVID-19 patients and was suspicious in the rest four remaining patients by NGS, but was negative in all serum samples. Proteomic analysis revealed that 185 and 59 proteins were differentially expressed in CSF and serum samples, respectively, and that only 20 proteins were shared, indicating that the proteomic changes in CSF were highly specific. Further proteomic annotation highlighted the involvement of complement system, PI3K-Akt signaling pathway, enhanced cellular interaction, and macrophages in the CSF proteomic alterations. This study, equipped with NGS and proteomics, reported a high detection rate of SARS-CoV-2 in the CSF of COVID-19 patients and the proteomic alteration of CSF, which would provide insights into understanding the pathological mechanism of SARS-CoV-2 CNS infection.

Viral and Prion Infections Associated with Central Nervous System Syndromes in Brazil.

Virus-induced infections of the central nervous system (CNS) are among the most serious problems in public health and can be associated with high rates of morbidity and mortality, mainly in low- and middle-income countries, where these manifestations have been neglected. Typically, herpes simplex virus 1 and 2, varicella-zoster, and enterovirus are responsible for a high number of cases in immunocompetent hosts, whereas other herpesviruses (for example, cytomegalovirus) are the most common in immunocompromised individuals. Arboviruses have also been associated with outbreaks with a high burden of neurological disorders, such as the Zika virus epidemic in Brazil. There is a current lack of understanding in Brazil about the most common viruses involved in CNS infections. In this review, we briefly summarize the most recent studies and findings associated with the CNS, in addition to epidemiological data that provide extensive information on the circulation and diversity of the most common neuro-invasive viruses in Brazil. We also highlight important aspects of the prion-associated diseases. This review provides readers with better knowledge of virus-associated CNS infections. A deeper understanding of these infections will support the improvement of the current surveillance strategies to allow the timely monitoring of the emergence/re-emergence of neurotropic viruses.

A comprehensive review of COVID-19 biology, diagnostics, therapeutics, and disease impacting the central nervous system.

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a highly transmissible disease. SARS-CoV-2 is estimated to have infected over 153 million people and to have caused over 3.2 million global deaths since its emergence in December 2019. SARS-CoV-2 is the seventh coronavirus known to infect humans, and like other coronaviruses, SARS-CoV-2 infection is characterized by a variety of symptoms including general flu-like symptoms such as a fever, sore throat, fatigue, and shortness of breath. Severe cases often display signs of pneumonia, lymphopenia, acute kidney injury, cardiac injury, cytokine storms, lung damage, acute respiratory distress syndrome (ARDS), multiple organ failure, sepsis, and death. There is evidence that around 30% of COVID-19 cases have central nervous system (CNS) or peripheral nervous system (PNS) symptoms along with or in the absence of the previously mentioned symptoms. In cases of CNS/PNS impairments, patients display dizziness, ataxia, seizure, nerve pain, and loss of taste and/or smell. This review highlights the neurological implications of SARS-CoV-2 and provides a comprehensive summary of the research done on SARS-CoV-2 pathology, diagnosis, therapeutics, and vaccines up to May 5.

Manifestations and mechanisms of central nervous system damage caused by SARS-CoV-2.

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its threat to humans have drawn worldwide attention. The acute and long-term effects of SARS-CoV-2 on the nervous system pose major public health challenges. Patients with SARS-CoV-2 present diverse symptoms of the central nervous system. Exploring the mechanism of coronavirus damage to the nervous system is essential for reducing the long-term neurological complications of COVID-19. Despite rapid progress in characterizing SARS-CoV-2, the long-term effects of COVID-19 on the brain remain unclear. The possible mechanisms of SARS-CoV-2 injury to the central nervous system include: 1) direct injury of nerve cells, 2) activation of the immune system and inflammatory cytokines caused by systemic infection, 3) a high affinity of the SARS-CoV-2 spike glycoprotein for the angiotensin-converting enzyme ACE2, 4) cerebrovascular disease caused by hypoxia and coagulation dysfunction, and 5) a systemic inflammatory response that promotes cognitive impairment and neurodegenerative diseases. Although we do not fully understand the mechanism by which SARS-CoV-2 causes nerve injury, we hope to provide a framework by reviewing the clinical manifestations, complications, and possible mechanisms of neurological damage caused by SARS-CoV-2. With hope, this will facilitate the early identification, diagnosis, and treatment of possible neurological sequelae, which could contribute toward improving patient prognosis and preventing transmission.

COVID-19 and neuroinflammation: a literature review of relevant neuroimaging and CSF markers in central nervous system inflammatory disorders from SARS-COV2.

BACKGROUND: The literature on neurological manifestations in COVID-19 patients has been rapidly increasing with the pandemic. However, data on CNS inflammatory disorders in COVID-19 are still evolving. We performed a literature review of CNS inflammatory disorders associated with coronavirus disease-2019 (COVID-19). METHODS: We screened all articles resulting from a search of PubMed, Google Scholar and Scopus, using the keywords; "SARS-CoV-2 and neurological complication", "SARS-CoV-2 and CNS Complication" looking for reports of transverse myelitis, longitudinally extensive transverse myelitis, neuromyelitis optica, myelitis, Myelin Oligodendrocyte Glycoprotein Antibody Disorder (MOGAD), Acute Disseminated Encephalomyelitis (ADEM), Acute Hemorrhagic Necrotizing Encephalitis/Acute Hemorrhagic Leukoencephalitis (AHNE/AHLE), Cytotoxic lesion of the Corpus Callosum/Mild Encephalopathy Reversible Splenium Lesion(CLOCC/MERS) and Optic neuritis published between December 01, 2019 and March 15, 2021. RESULTS: Our literature search revealed 43 patients meeting the diagnosis of myelitis, including Transverse Myelitis, ADEM, AHNE/AHLE or CLOCC/MERS and Optic neuritis. Acute myelitis was most commonly associated with non-severe COVID-19 and all reported cases of AHNE/AHLE had severe COVID-19 infection. Based on IDSA/ATS criteria of either requiring vasopressor for septic shock or mechanical ventilation, 49% (n = 18) patients were considered to have a severe COVID infection. There were 7 (n = 19%) fatalities. CONCLUSION: To our knowledge, this is among the first reviews that includes the clinical features, neuroimaging, CSF findings and outcomes in COVID-19-associated CNS inflammatory disorders. Our observational review study reveals that although rare, myelitis, ADEM, AHNE and CLOCC can be associated with COVID-19 infection. Further studies using MRI imaging and CSF analysis in early diagnosis and intervention of these disorders are warranted.

New onset neurologic events in people with COVID-19 in 3 regions in China.

OBJECTIVE: To investigate new-onset neurologic impairments associated with coronavirus disease 2019 (COVID-19). METHODS: A retrospective multicenter cohort study was conducted between January 18 and March 20, 2020, including people with confirmed COVID-19 from 56 hospitals officially designated in 3 Chinese regions; data were extracted from medical records. New-onset neurologic events as assessed by neurology consultants based on manifestations, clinical examination, and investigations were noted, in which critical events included disorders of consciousness, stroke, CNS infection, seizures, and status epilepticus. RESULTS: We enrolled 917 people with average age 48.7 years and 55% were male. The frequency of new-onset critical neurologic events was 3.5% (32/917) overall and 9.4% (30/319) among those with severe or critical COVID-19. These were impaired consciousness (n = 25) or stroke (n = 10). The risk of critical neurologic events was highly associated with age above 60 years and previous history of neurologic conditions. Noncritical events were seen in fewer than 1% (7/917), including muscle cramp, unexplained headache, occipital neuralgia, tic, and tremor. Brain CT in 28 people led to new findings in 9. Findings from lumbar puncture in 3 with suspected CNS infection, unexplained headache, or severe occipital neuralgia were unremarkable. CONCLUSIONS: People with COVID-19 aged over 60 and with neurologic comorbidities were at higher risk of developing critical neurologic impairment, mainly impaired consciousness and cerebrovascular accidents. Brain CT should be considered when new-onset brain injury is suspected, especially in people under sedation or showing an unexplained decline in consciousness. Evidence of direct acute insult of severe acute respiratory syndrome coronavirus 2 to the CNS is lacking.

Proteomic blood profiling in mild, severe and critical COVID-19 patients.

The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in most individuals, leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. This study explores the proteomic differences between mild, severe, and critical COVID-19 positive patients to further understand the disease progression, identify proteins associated with disease severity, and identify potential therapeutic targets. Blood protein profiling was performed on 59 COVID-19 mild (n = 26), severe (n = 9) or critical (n = 24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/ . Our results demonstrate that dynamic changes in blood proteins associated with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic targets.

Interactions of SARS-CoV-2 with the Blood-Brain Barrier.

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood-brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.

SARS-CoV-2 journey to the brain with a focus on potential role of docosahexaenoic acid bioactive lipid mediators.

Coronavirus Disease 2019 or COVID-19 have infected till day 82,579,768 confirmed cases including 1,818,849 deaths, reported by World Health Organization WHO. COVID-19, originated by Severe Acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), contributes to respiratory distress in addition to neurological symptoms in some patients. In the current review, we focused on the neurological complications associated with COVID-19. We discussed different pathways followed by RNA-virus, especially Flaviviridae family in the brain and passage through the Blood-Brain-Barrier BBB. Then, we explored SARS-CoV-2 mechanisms responsible of neuroinvasion and BBB disruption as well as the immunopathogenesis of SARS-CoV-2 in the central nervous system CNS. Since SARS-CoV-2 is an enveloped virus, enclosed in a lipid bilayer and that lipids are essential cell components playing numerous biological roles in viral infection and replication, we investigated the lipid metabolism remodeling upon coronavirus replication. We also highlighted the anti-inflammatory and neuroprotective potential of an omega-3 polyunsaturated fatty acid, docosahexaenoic acid DHA, as well as several bioactive lipid mediators. Altogether, our data allow better understanding of SARS-CoV-2 neuroinvasion and could assist in drug targeting to decline the burden of short-term and long-term neurological manifestations of SARS-CoV-2.

Central nervous system manifestations in COVID-19 patients: A systematic review and meta-analysis.

BACKGROUND: At the end of December 2019, a novel respiratory infection, initially reported in China, known as COVID-19 initially reported in China, and later known as COVID-19, led to a global pandemic. Despite many studies reporting respiratory infections as the primary manifestations of this illness, an increasing number of investigations have focused on the central nervous system (CNS) manifestations in COVID-19. In this study, we aimed to evaluate the CNS presentations in COVID-19 patients in an attempt to identify the common CNS features and provide a better overview to tackle this new pandemic. METHODS: In this systematic review and meta-analysis, we searched PubMed, Web of Science, Ovid, EMBASE, Scopus, and Google Scholar. Included studies were publications that reported the CNS features between 1 January 2020 and 20 April 2020. The data of selected studies were screened and extracted independently by four reviewers. Extracted data analyzed by using STATA statistical software. The study protocol registered with PROSPERO (CRD42020184456). RESULTS: Of 2,353 retrieved studies, we selected 64 studies with 11,687 patients after screening. Most of the studies were conducted in China (58 studies). The most common CNS symptom of COVID-19 was headache (8.69%, 95%CI: 6.76%-10.82%), dizziness (5.94%, 95%CI: 3.66%-8.22%), and impaired consciousness (1.90%, 95%CI: 1.0%-2.79%). CONCLUSIONS: The growing number of studies has reported COVID-19, CNS presentations as remarkable manifestations that happen. Hence, understanding the CNS characteristics of COVID-19 can help us for better diagnosis and ultimately prevention of worse outcomes.

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms.

BACKGROUND: COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity. DESIGN: Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies. RESULTS: Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb. CONCLUSION: The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.

Neurological manifestations of COVID-19: a systematic review and meta-analysis of proportions.

BACKGROUND: Coronaviruses mainly affect the respiratory system; however, there are reports of SARS-CoV and MERS-CoV causing neurological manifestations. We aimed at discussing the various neurological manifestations of SARS-CoV-2 infection and to estimate the prevalence of each of them. METHODS: We searched the following electronic databases; PubMed, MEDLINE, Scopus, EMBASE, Google Scholar, EBSCO, Web of Science, Cochrane Library, WHO database, and ClinicalTrials.gov . Relevant MeSH terms for COVID-19 and neurological manifestations were used. Randomized controlled trials, non-randomized controlled trials, case-control studies, cohort studies, cross-sectional studies, case series, and case reports were included in the study. To estimate the overall proportion of each neurological manifestations, the study employed meta-analysis of proportions using a random-effects model. RESULTS: Pooled prevalence of each neurological manifestations are, smell disturbances (35.8%; 95% CI 21.4-50.2), taste disturbances (38.5%; 95%CI 24.0-53.0), myalgia (19.3%; 95% CI 15.1-23.6), headache (14.7%; 95% CI 10.4-18.9), dizziness (6.1%; 95% CI 3.1-9.2), and syncope (1.8%; 95% CI 0.9-4.6). Pooled prevalence of acute cerebrovascular disease was (2.3%; 95%CI 1.0-3.6), of which majority were ischaemic stroke (2.1%; 95% CI 0.9-3.3), followed by haemorrhagic stroke (0.4%; 95% CI 0.2-0.6), and cerebral venous thrombosis (0.3%; 95% CI 0.1-0.6). CONCLUSIONS: Neurological symptoms are common in SARS-CoV-2 infection, and from the large number of cases reported from all over the world daily, the prevalence of neurological features might increase again. Identifying some neurological manifestations like smell and taste disturbances can be used to screen patients with COVID-19 so that early identification and isolation is possible.

Neurological manifestations and comorbidity associated with COVID-19: an overview.

First in 2002, severe acute respiratory syndrome coronavirus (SARS-CoV), second in 2012, Middle East respiratory syndrome coronavirus (MERS-CoV), and now the third in the December 2019, emergence of tremendously pathogenic and large-scale epidemic novel coronavirus (SARS-CoV-2) has brought the worst conditions into the human inhabitants of the twenty-first century. The SARS-CoV-2 uses the resembling receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly feasts through the respiratory tract. The ACE2 receptor appearances have been also detected upon glial cells and neurons, which makes them a potential target of SARS-CoV-2 disease (COVID-19). Consequently, cells expressing ACE2, apart from lung and cardiovascular tissue, neurons and glial cells may act as targets and are thus vulnerable to SARS-CoV-2 systemic infection as well as its central nervous system (CNS) comorbidities. Investigation of the neurological manifestations of COVID-19 is a step towards better understanding the SARS-CoV-2 infections, inhibiting the additional spread and treating patients affected by this pandemic. In this concern, more clinical examinations for CNS involvement of SARS-CoV-2 are warranted. In this article, we have reviewed the neurological characteristic features of COVID-19 patients, latent neurotropic mechanisms of SARS-CoV-2 involvement in the comorbidity associated with CNS disorders, and neurological manifestations associated with COVID-19. Therefore, in the perspective of COVID-19 pandemic, clinicians and healthcare workers should be aware of a wide spectrum of neurological manifestations associated with COVID-19 along with their signs and symptoms for initial diagnosis and isolation of the patients.

Beneficial and Detrimental Effects of Regulatory T Cells in Neurotropic Virus Infections.

Neurotropic viruses infect the central nervous system (CNS) and cause acute or chronic neurologic disabilities. Regulatory T cells (Treg) play a critical role for immune homeostasis, but may inhibit pathogen-specific immunity in infectious disorders. The present review summarizes the current knowledge about Treg in human CNS infections and their animal models. Besides dampening pathogen-induced immunopathology, Treg have the ability to facilitate protective responses by supporting effector T cell trafficking to the infection site and the development of resident memory T cells. Moreover, Treg can reduce virus replication by inducing apoptosis of infected macrophages and attenuate neurotoxic astrogliosis and pro-inflammatory microglial responses. By contrast, detrimental effects of Treg are caused by suppression of antiviral immunity, allowing for virus persistence and latency. Opposing disease outcomes following Treg manipulation in different models might be attributed to differences in technique and timing of intervention, infection route, genetic background, and the host's age. In addition, mouse models of virus-induced demyelination revealed that Treg are able to reduce autoimmunity and immune-mediated CNS damage in a disease phase-dependent manner. Understanding the unique properties of Treg and their complex interplay with effector cells represents a prerequisite for the development of new therapeutic approaches in neurotropic virus infections.

Neurological Complications Associated with the Blood-Brain Barrier Damage Induced by the Inflammatory Response During SARS-CoV-2 Infection.

The main discussion above of the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has focused substantially on the immediate risks and impact on the respiratory system; however, the effects induced to the central nervous system are currently unknown. Some authors have suggested that SARS-CoV-2 infection can dramatically affect brain function and exacerbate neurodegenerative diseases in patients, but the mechanisms have not been entirely described. In this review, we gather information from past and actual studies on coronaviruses that informed neurological dysfunction and brain damage. Then, we analyzed and described the possible mechanisms causative of brain injury after SARS-CoV-2 infection. We proposed that potential routes of SARS-CoV-2 neuro-invasion are determinant factors in the process. We considered that the hematogenous route of infection can directly affect the brain microvascular endothelium cells that integrate the blood-brain barrier and be fundamental in initiation of brain damage. Additionally, activation of the inflammatory response against the infection represents a critical step on injury induction of the brain tissue. Consequently, the virus' ability to infect brain cells and induce the inflammatory response can promote or increase the risk to acquire central nervous system diseases. Here, we contribute to the understanding of the neurological conditions found in patients with SARS-CoV-2 infection and its association with the blood-brain barrier integrity.

Dyspneic and non-dyspneic (silent) hypoxemia in COVID-19: Possible neurological mechanism.

SARS-CoV-2 mainly invades respiratory epithelial cells by adhesion to angiotensin-converting enzyme 2 (ACE-2) and thus, infected patients may develop mild to severe inflammatory responses and acute lung injury. Afferent impulses that result from the stimulation of pulmonary mechano-chemoreceptors, peripheral and central chemoreceptors by inflammatory cytokines are conducted to the brainstem. Integration and processing of these input signals occur within the central nervous system, especially in the limbic system and sensorimotor cortex, and importantly feedback regulation exists between O2, CO2, and blood pH. Despite the intensity of hypoxemia in COVID-19, the intensity of dyspnea sensation is inappropriate to the degree of hypoxemia in some patients (silent hypoxemia). We hypothesize that SARS-CoV-2 may cause neuronal damage in the corticolimbic network and subsequently alter the perception of dyspnea and the control of respiration. SARS-CoV-2 neuronal infection may change the secretion of numerous endogenous neuropeptides or neurotransmitters that distribute through large areas of the nervous system to produce cellular and perceptual effects. SARS-CoV-2 mainly enter to CNS via direct (neuronal and hematologic route) and indirect route. We theorize that SARS-CoV-2 infection-induced neuronal cell damage and may change the balance of endogenous neuropeptides or neurotransmitters that distribute through large areas of the nervous system to produce cellular and perceptual effects. Thus, SARS-CoV-2-associated neuronal damage may influence the control of respiration by interacting in neuromodulation. This would open up possible lines of study for the progress in the central mechanism of COVID-19-induced hypoxia. Future research is desirable to confirm or disprove such a hypothesis.

Correlation between CNS Tuberculosis and the COVID-19 Pandemic: The Neurological and Therapeutic Insights.

The recent outbreak of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) from Wuhan, China, was caused by a single-stranded RNA virus which has kept the entire world stranded. The outbreak was first diagnosed with respiratory illness, but recent findings of acute necrotizing hemorrhage of brain, brain encephalopathy, and the presence of the virus in the cerebrospinal fluid (CSF) have unveiled its neuroinvasivness. Various clinical features related to the central nervous system (CNS) and peripheral nervous system (PNS) due to COVID-19 infection are now identified. We demonstrate here an apparent similarity in neurological disorders of COVID-19 with CNS tuberculosis, which suggests that some anti-tubercular drugs may be used as therapeutic agents against COVID-19 infection.

Central Nervous System Targets and Routes for SARS-CoV-2: Current Views and New Hypotheses.

As the coronavirus disease 2019 (COVID-19) pandemic unfolds, neurological signs and symptoms reflect the involvement of targets beyond the primary lung effects. The etiological agent of COVID-19, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits neurotropism for central and peripheral nervous systems. Various infective mechanisms and paths can be exploited by the virus to reach the central nervous system, some of which bypass the blood-brain barrier; others alter its integrity. Numerous studies have established beyond doubt that the membrane-bound metalloprotease angiotensin-converting enzyme 2 (ACE2) performs the role of SARS-CoV-2 host-cell receptor. Histochemical studies and more recently transcriptomics of mRNA have dissected the cellular localization of the ACE2 enzyme in various tissues, including the central nervous system. Epithelial cells lining the nasal mucosae, the upper respiratory tract, and the oral cavity, bronchoalveolar cells type II in the pulmonary parenchyma, and intestinal enterocytes display ACE2 binding sites at their cell surfaces, making these epithelial mucosae the most likely viral entry points. Neuronal and glial cells and endothelial cells in the central nervous system also express ACE2. This short review analyzes the known entry points and routes followed by the SARS-CoV-2 to reach the central nervous system and postulates new hypothetical pathways stemming from the enterocytes lining the intestinal lumen.