Coronaviruses and the central nervous system

Abstract

Seven coronavirus (CoV) species are known human pathogens: the epidemic viruses SARS-CoV, SARS-CoV-2, and MERS-CoV and those continuously circulating in human populations since initial isolation: HCoV-OC43, HCoV-229E, HCoV-HKU1, and HCoV-NL63. All have associations with human central nervous system (CNS) dysfunction. In infants and young children, the most common CNS phenomena are febrile seizures; in adults, non-focal abnormalities that may be either neurologic or constitutional. Neurotropism and neurovirulence are dependent in part on CNS expression of cell surface receptors mediating viral entry, and host immune response. In adults, CNS receptors for epidemic viruses are largely expressed on brain vasculature, whereas receptors for less pathogenic viruses are present in vasculature, brain parenchyma, and olfactory neuroepithelium, dependent upon viral species. Human coronaviruses can infect circulating mononuclear cells, but meningoencephalitis is rare. Well-documented human neuropathologies are infrequent and, for SARS, MERS, and COVID-19, can entail cerebrovascular accidents originating extrinsically to brain. There is evidence of neuronal infection in the absence of inflammatory infiltrates with SARS-CoV, and CSF studies of rare patients with seizures have demonstrated virus but no pleocytosis. In contrast to human disease, animal models of neuropathogenesis are well developed, and pathologies including demyelination, neuronal necrosis, and meningoencephalitis are seen with both native CoVs as well as human CoVs inoculated into nasal cavities or brain. This review covers basic CoV biology pertinent to CNS disease; the spectrum of clinical abnormalities encountered in infants, children, and adults; and the evidence for CoV infection of human brain, with reference to pertinent animal models of neuropathogenesis.

Keywords: Central nervous system; Coronavirus; Neurologic disease.

Fig. 1

a Canonical organization of the coronavirus genome. Major genes present in all coronaviruses, from 5′ to 3′, encode the replicase/transcriptase complex, the spike (S) protein, the envelope (E) protein, the membrane (M) protein, and the nucleocapsid protein (N). In some variants, a fifth major protein, the hemagglutinin-esterase (HE), is represented proximal to the spike protein. b Organization of the coronavirus virion. S, E, and M proteins are embedded in the membrane envelope, whereas the N protein encases the viral genome

Fig. 2

Cell entry pathways utilized by coronaviruses. Coronaviruses enter cell cytoplasm via two receptor-mediated pathways that require proteolytic processing of the S protein; this priming exposes the S2 domain, which participates in membrane fusion and allows injection of viral genome into the cell. The “early pathway” occurs exclusively at the cell membrane, and the “late pathway” entails viral internalization via clathrin-coated pits that transition to acidified endosomes. In the late pathway, S antigen priming occurs both at the cell membrane (via proteases such as TMPRSS2 and furin), as well as in the endosome, utilizing endosomal proteases (cathepsins) and potentially furin. Therapies that interfere with acidification of the endosome, such as hydroxychloroquine, interfere with this pathway. In the early pathway, viral binding to the receptor and proteolytic processing of the S protein are accomplished entirely by proteases at the cell surface, which allows direct entry of the viral genome into cytoplasm.

Fig. 3

COVID-19-associated microangiopathy in the brain. This high-power photomicrograph displays a small blood vessel in cerebral white matter of a patient dying with COVID-19 disease. A small fibrin thrombus is seen, and monocyte margination consistent with “endotheliitis” as has been described in systemic vasculature. This patient had infarcts and hemorrhages; these findings were the most common abnormalities in the largest neuropathology series described to date (Bryce et al. 2020). (Hematoxylin and eosin stain, original magnification 200×)