Does SARS‐Cov‐2 invade the brain? Translational lessons from animal models

Abstract

The current coronavirus disease (COVID‐19) outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has raised the possibility of potential neurotropic properties of this virus. Indeed, neurological sequelae of SARS‐CoV‐2 infection have already been reported and highlight the relevance of considering the neurological impact of coronavirus (CoV) from a translational perspective. Animal models of SARS and Middle East respiratory syndrome, caused by structurally similar CoVs during the 2002 and 2012 epidemics, have provided valuable data on nervous system involvement by CoVs and the potential for central nervous system spread of SARS‐CoV‐2. One key finding that may unify these pathogens is that all require angiotensin‐converting enzyme 2 as a cell entry receptor. The CoV spike glycoprotein, by which SARS‐CoV‐2 binds to cell membranes, binds angiotensin‐converting enzyme 2 with a higher affinity compared with SARS‐CoV. The expression of this receptor in neurons and endothelial cells hints that SARS‐CoV‐2 may have higher neuroinvasive potential compared with previous CoVs. However, it remains to be determined how such invasiveness might contribute to respiratory failure or cause direct neurological damage. Both direct and indirect mechanisms may be of relevance. Clinical heterogeneity potentially driven by differential host immune‐mediated responses will require extensive investigation. Development of disease models to anticipate emerging neurological complications and to explore mechanisms of direct or immune‐mediated pathogenicity in the short and medium term is therefore of great importance. In this brief review, we describe the current knowledge from models of previous CoV infections and discuss their potential relevance to COVID‐19.

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

“…On the other hand, the idea that SARS-CoV-2 could infect the brain through peripheral nerves, and specifically an olfactory route, has been raised by several authors, both in light of the anosmia observed in COVID-19 patients (40,41) and from experimental animal studies on SARS-CoV (42,43). In the latter, SARS-CoV administered intranasally was found in the hypothalamus and brainstem within days, a determining factor for mortality (43).…”

“…Once in the bloodstream, the virus could also access other parts of the brain through a leaky endothelial barrier, or other CVOs such as the organum vasculosum of the lamina terminalis, the subfornical organ or the area postrema (35), all of which play key roles in either the risk factors or the physiological functions targeted by SARS-CoV-2. While the AHBA does not allow gene expression in these CVOs to be analyzed, further immunolabeling experiments may provide evidence for viral targeting.On the other hand, the idea that SARS-CoV-2 could infect the brain through peripheral nerves, and specifically an olfactory route, has been raised by several authors, both in light of the anosmia observed in 41) and from experimental animal studies on 43). In the latter, SARS-CoV administered intranasally was found in the hypothalamus and brainstem within days, a determining factor for mortality (43).…”

Of mice and men: COVID‐19 challenges translational neuroscience

“…The animal studies also provided hints for the potential routes of CNS entry, i.e. olfactory bulbs, peripheral nerves, synapseconnected route from the lungs to the medullary cardiorespiratory center and hematogenic spread [4]. The animal experiments furthermore identified that features of CoV CNS infection include a key role for the innate immune system, impact of aging and an earlier viral clearance in animal models.…”

“…To fill this knowledge gap about the potential neuroinvasiveness and route of central nervous system (CNS) entry, Silvia Natoli and collaborators went back to the scientific literature on animal models of SARS-CoV and Middle East respiratory syndrome virus [4]. They studied whether there is evidence for neuropathogenesis in experimental studies of these structurally similar CoVs, which were responsible for the epidemics with severe respiratory disease in 2002 and 2012, respectively.…”

Management of Patients with Cerebellar Ataxia During the COVID-19 Pandemic: Current Concerns and Future Implications

“…SARS-CoV2 requires the angiotensinconverting enzyme 2 (ACE2) to enter cells. This receptor is expressed in endothelial cells and neurons, which indicates that it has neuroinvasive potential [4].…”