A new study by researchers from the University of California-Davis, USA involving animal models such as the Rhesus Macaques has found that SARS-CoV-2 coronavirus is able to infect the neurons of the brain and induce inflammation.
The study findings were published in the peer reviewed journal: Cell Reports as journal pre-proof.
https://www.cell.com/cell-reports/pdf/S2211-1247(22)01434-6.pdf
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 Fig. 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 COVID-19 patients 3,19–21.
Furthermore, the impact on olfactory pathways is consistent with the persistent anosmia observed in some COVID-19 patients26. 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.
Our observations are remarkably similar to those of Rutkai et al. (2022)27, who found morphological changes in microglia consistent with activation, evidence of astrogliosis, and vascular homeostasis disruptions at 28 days post-infection. 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 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 COVID-19 patients 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 models28.
Moreover, several early reports indicate that older patients experience neurological symptoms with increased severity and frequency, including complex neurological presentations unique to this population29. 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.
Limitations of this Study
Some limitations of this study should be acknowledged. This study employs a group of aged animals (18-24 years old) with type 2 diabetes combined with other comorbidities, an experimental group designed to mimic the clinical complexity of older human patients infected with SARS-CoV-2.
Data obtained from these animals should be interpreted with care, as there is an intrinsic challenge to dissociating the effects of aging, T2D, and other comorbidities. The limited supply of spontaneous T2D animals in our colony has constrained our ability to include more T2D controls, forcing us to compare data between aged diabetic and aged non-diabetic animals. Nevertheless, our diabetic controls have shown consistent results with those obtained in non-diabetic controls.
The overall number of animals was also constrained as a whole due to cost and infrastructure limitations associated with keeping Rhesus monkeys in A-BSL3 condition with complete veterinary care, even for a short period of time. To improve the chances of viral detection within the olfactory cortex 7 days after infection, we used a high dose of SARS-CoV-2 and inoculated the virus intranasally and intratracheally, another important caveat of this study. In addition, the olfactory epithelium and olfactory bulbs of these animals were unavailable at the time of this study, precluding us from drawing definitive conclusions about the route SARS-CoV-2 uses to access the brain, despite substantial evidence for an olfactory entry.
