SARS-CoV-2 Infections Can Lead To Brain Inflammation – Hypoxia / Bleeding And Strokes

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Brain And SARS-CoV-2: A new study involving non-human primates by researchers from Tulane University School of Medicine, New Orleans-USA and Tulane National Primate Research Center-USA has alarmingly revealed that SARS-CoV-2 infections can cause brain inflammation, brain hypoxia, brain bleeding and also strokes.

he study findings were published on the peer reviewed journal: Nature Communications.

 https://www.nature.com/articles/s41467-022-29440-z

Neurological manifestations are commonly seen in the context of SARS-CoV-2 infection but are highly varied and range in severity from impaired smell and/or taste to stroke2,19. As such, the mechanisms underlying SARS-CoV-2-associated neurological complications are likely complex. Relevant animal models of infection and CNS involvement that reflect human disease are critical for elucidating these mechanisms, as well as identifying and/or developing effective therapeutic strategies.

In our two models of aged NHPs infected with SARS-CoV-2, we found evidence of prominent neuroinflammation, microhemorrhages with and without associated microthrombi, and neuronal injury and death consistent with hypoxic-ischemic injury but without substantial virus detection in brain. Our findings are largely in line with those reported in autopsy studies of individuals who died from infection 20,21,22,23,24,25,26.

Like human disease, reactive astrocytes and microglia were a common feature, seen throughout the entirety of the brain in infected animals. This appeared greater in basal ganglia, brainstem, and cerebellum, which contained the majority of cuffs and nodular lesions observed.

Lymphocyte infiltrate, which has been reported in human brain 22,24, was not observed in any brain region investigated from our study animals. This may reflect a shorter time with severe disease in our animal model. Additional life-saving efforts were not made for animals that developed serious disease (e.g., ARDS), as would be done with humans, and were quickly euthanized to minimize pain and suffering of the animal. It is worth noting that autopsy reports of significant lymphocyte infiltration into the CNS or COVID-associated encephalitis are relatively few and may be a less common complication of disease8.

Our findings of hypoxic-ischemic injury in brain of NHPs are also in agreement with autopsy studies of brain from human subjects21,27. This may arise from chronic, peripheral hypoxemia, as well as reduced cerebral blood flow due to acute microhemorrhages. The brain is a highly metabolic organ and requires aerobic metabolism of glucose for adenosine triphosphate (ATP) production.

Any prolonged or chronic intermittent reductions of blood SpO2 may contribute to localized CNS hypoxia and energy failure. Even minor, but sustained, reductions in oxygen may promote injury, particularly among neurons, which appear to have suffered the greatest insult in this study. In support of this notion, large stretches of Purkinje cells, which are especially vulnerable to hypoxic insult13,14, as well as cells within their immediate proximity, appear degenerate and/or committed to undergoing apoptosis.

Areas of injured neurons at various stages of nuclear dissolution were noted in other brain regions, including brainstem. Moreover, neuronal injury did not appear to be a direct consequence of virus infection, as only limited virus was convincingly detected in brain vasculature and did not appear to involve parenchymal cells.

Instead, neuronal injury and death most likely occur as a result of energy failure, which is an early consequence of hypoxic-ischemic events. Multiple microhemorrhages, microinfarcts, and hypoxemia appear to play a role in neuronal injury and death observed in these animals.

Consistent with a hypoxic environment, we detected upregulation/stabilization of HIF-1a in infected animals that localized to the brain vasculature and was significantly greater than mock-infected controls in the deep brain regions assessed. This was observed in all infected animals, regardless of disease severity, suggesting reduced brain oxygen may be a common complication of infection.

While the mechanism is not yet elucidated, chronic hypoxemia, as well as an exaggerated and prolonged immune response likely play an important role. Indeed, several inflammatory mediators and growth factors have been reported to stabilize and/or promote expression of HIF-1a, including nitric oxide, interleukin 1b, and tumor necrosis factor-a 28,29,30.

Interestingly, we did not observe HIF-1a upregulation in cerebellar Purkinje cells in any animal. This may be due to the kinetics of HIF-1a expression, which has been shown in a mouse model of chronic hypoxia to peak in Purkinje cells at 4–5 h and return to normoxic levels after 9–12 h in a continual hypoxic environment31.

These findings suggest that any potential upregulation and/or stabilization of HIF-1a in Purkinje cells had returned to normal levels by the time the animals were euthanized. It is also likely that degenerate Purkinje cells no longer produce HIF-1a. Our conflicting findings in the brain vasculature may be due to continued exposure of these cells to peripheral factors that promote HIF-1a stabilization and/or expression.

A direct role for the virus in HIF-1a upregulation cannot be ruled out, however, the negligible frequency of SARS-CoV-2 infected cells seen in the CNS compartment argues against the virus being a significant factor. A recent RNAseq analysis, however, found increased HIF-1a mRNA in peripheral blood mononuclear cells (PBMC) acquired from SARS-CoV-2 infected human subjects, as compared to healthy, non-infected controls32. Additional in vitro analyses suggested SARS-CoV-2 ORF3a protein induces HIF-1a production in transfected cells, as well as several cytokines upregulated in the context of infection32. How this translates to HIF-1a expression in vivo, however, remains unclear.

In agreement with most reports of living subjects and those who died from COVID-19 8, we did not detect virus in CSF and found only minimal virus in the brain that appeared to be limited to the vasculature, suggestive of hematological dissemination of virus to the brain. Infection of pericytes, perivascular macrophages, and/or cells within the brain parenchyma cannot be ruled out but was not convincingly demonstrated in these studies.

Instead, virus appeared to be restricted to the endothelium, which is consistent with a previous study of human biopsy tissues that demonstrated the principal receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is expressed by endothelial cells throughout the body, including brain33,34. More recently, a large autopsy series out of Mount Sinai demonstrated robust ACE2 expression by brain vasculature in patients who died from SARS-CoV-2 infection20.

This may suggest a greater vulnerability of the brain to infection in the context of severe disease but was not observed in NHPs that developed ARDS in this study. One autopsy report identified virus in a subset of cranial nerves22, however, these were not available for investigation. Additionally, the olfactory bulb, which was not recovered from our study animals, may also be an important site for virus entry into the CNS and requires additional investigation.

Notably, the animals in this study were of advanced age, which is associated with a higher risk for the development of cerebrovascular disease among infected patients8. Indeed, aging, itself, is the greatest risk factor for cerebrovascular disease, due, at least in part to age-related changes of cerebral vascular structure and/or function that contribute to reduced cerebral blood flow, which may be further compounded by underlying vascular pathology 35,36.

This may predispose the aging vasculature to cerebrovascular events, particularly in the context of prolonged systemic inflammation and hypoxemia, which have been shown to contribute to increased vascular permeability through microglia and astrocyte responses 37,38.

Here, we show substantial pathological changes in brain of SARS-CoV-2 infected NHPs that are compatible with autopsy and imaging reports of infected human subjects. Additionally, our pathological investigation suggests a significant role for brain hypoxia in the neuropathogenesis of COVID-19, including animals without severe disease. It is reasonable to anticipate that similar findings may occur among human subjects, particularly those with continuing neurological symptoms after recovery from infection39,40,41.

For example, an increasing number of retrospective neuroimaging reports have reported cerebral microhemorrhages in critically ill patients with COVID-1942,43,44. Many patients, however, including those who do not require hospitalization, report comparatively milder neurological symptoms that are not evaluated through neuroimaging.

As such, neuropathology among these individuals remains unclear but likely contributes to lingering neurocognitive difficulties reported by a number of convalesced/convalescing patients 45 and warrants further investigation. This further increases the significance of NHPs as a viable model for elucidating the mechanisms that underlie SARS-CoV-2-associated neuropathology that are translatable to human disease, as neuropathogenesis can be more closely examined in animals that do not experience mortal disease.

Additionally, neuropathological complications may contribute to worsening disease among infected patients. For example, damage to the brainstem, which modulates the respiratory cycle by regulating inspiratory and expiratory muscle activity, may contribute to worsening respiratory distress and failure in patients with COVID-19. Additional studies, employing relevant animal models, are warranted and likely to reveal important insight into human disease.

While SARS-CoV-2 neuropathogenic processes are poorly understood, this work reveals infected NHPs are a viable animal model for understanding the neuropathogenesis and potential long-term consequences of infection. We also provide important insight into the mechanisms underlying CNS disease, which was seen even in the absence of severe respiratory disease and may suggest that vascular leakage and hypoxic brain injury is a common complication of SARS-CoV-2 infection and COVID-19.

Neuronal degeneration and activation of caspase 3 observed in this study supports this notion and indicates non-reversible neuronal injury may be significant to individuals suffering from PASC. Finally, our findings and conclusions presented herein suggest the need for long-term neurological follow-up of persistently symptomatic convalescent patients.

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