SARS-CoV-2 Causes Neuroinflammation

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A new study by researchers from the University of California- Davis, USA involving rhesus macaques (Macaca mulatta) of Indian origin has demonstrated that SARS-CoV-2 infections induces neuroinflammation.

The study findings provide an initial framework for identifying the molecular and cellular mechanisms underlying SARS-CoV-2 neurological complications, which will be essential to reducing both the short- and long-term burden of COVID-19.
 
The study findings were published in the peer reviewed journal: Cell Reports.
https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01434-6

Figure 3SARS-CoV-2 infection induces blood vessel disruption, reactive neutrophil recruitment, and ACE2 receptor downregulation

In the present study, we have investigated the presence of SARS-CoV-2-related proteins in the brains of rhesus monkeys at 7 days post inoculation to see the neurotropic potential of SARS-CoV-2 at this early point in the course of the infection in a non-human primate.

The overwhelming predominance of productive neuronal infection, combined with the spatially restricted distribution of viral proteins to the olfactory circuit, suggests the fast transneuronal spread of SARS-CoV-2 along corticocortical pathways, leading to its dissemination within the CNS via the olfactory connectome (summarized in Figure 4).

This observation is in good agreement with previous reports that have demonstrated a similar progression pattern in laboratory animals for other human coronaviruses, such as HCoV-OC43 and HCoV-229E, and it closely matches the areas of decreased gray-matter thickness in human patients with COVID-19.3,19,20,21

Furthermore, the impact on olfactory pathways is consistent with the persistent anosmia observed in some patients with COVID-19.26

We cannot exclude, however, the possibility that the virus reaches the CNS through other pathways (e.g., vascular breakdown, translocation of infected immune cells) at later stages of the infection.

Figure 4Summary of the anatomical localization, cell type, and viral protein spread observed in SARS-CoV-2-infected monkeys

The results found in this work also indicate that the presence of SARS-CoV-2-related proteins within the olfactory pathway is accompanied by extensive microglial and astrocytic changes typically associated with neuroinflammatory responses, including alterations in cellular volume, morphology, and populational density, in addition to abnormal blood vessels and infiltration of activated neutrophils.

Our observations are remarkably similar to those of Rutkai et al.,27 who found morphological changes in microglia consistent with activation, evidence of astrogliosis, and vascular homeostasis disruptions at 28 dpi. Combined, these works suggest that neuroinflammatory changes happen early during the course of the disease and can remain in place for an extended period of time, even if viral proteins are eliminated after the acute stage of the disease.

Importantly, in aged animals, neuroinflammation was accompanied by synaptic engulfment and myelin degradation in areas exhibiting a high density of HLA-DR+ microglia, suggesting that demyelinating lesions and synaptic loss could be early deleterious effects resulting from an exacerbated neuroinflammatory response that can persist for several weeks.

This process may explain why some patients with COVID-19 experience neurological symptoms, even in the absence of severe respiratory disease, and it underscores the potential for anti-neuroinflammatory agents in the control of COVID-19-related neurological sequelae.

The importance of the more widespread and severe neuronal infection by SARS-CoV-2 and the corresponding increased neuroinflammatory response observed in aged macaques with T2D and other comorbidities should not be understated. Older patients with diabetes (and other age-related comorbidities) are the most vulnerable population regarding COVID-19 severity and lethality, reinforcing the need to represent this complex group of individuals in translational animal models.28

Moreover, several early reports indicate that older patients experience neurological symptoms with increased severity and frequency, including complex neurological presentations unique to this population.29 Our work suggests that viral infection and senescence/comorbidities lead to synergistic damage to central nervous function, helping explain the uniqueness of this group regarding neurologic complications in COVID-19.

We have also identified dsRNA and SARS-CoV-2 proteins in the entorhinal cortex of our experimental model of aged macaques, a cortical region particularly vulnerable to tauopathy associated with Alzheimer’s disease (AD).

Considering the short period of time investigated in this work, it is likely that SARS-CoV-2 eventually reaches the same temporal and frontal cortical fields that are affected in AD, with yet unknown consequences. More studies will be necessary to understand the temporal course of the infection, as well as its implications for long-term neurological sequelae and potentially dementia.

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