New Non-Human Primate Study Alarmingly Reveals That SARS-CoV-2 Infections Can Lead To Brain Inflammation, Brain Hypoxia, Brain Bleeding And Also Strokes!

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!


 
To date, a variety of neurological manifestations are a significant complication of coronavirus disease (COVID-19), but underlying mechanisms aren’t well understood.
 
The development of animal models that recapitulate the neuropathological findings of autopsied brain tissue from patients who died from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are critical for elucidating the neuropathogenesis of infection and disease.
 
The study team alarmingly found neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis.
 
What is shocking was that these manifestations were witnessed among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with “long COVID”.
 
It was also noted that the sparse virus is detected in brain endothelial cells did not correlate with the severity of central nervous system (CNS) injury.
 
The Brain-SARS-CoV-2 study team hopes that the research findings will advance the current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.
 
The study findings were published on the peer reviewed journal: Nature Communications. https://www.nature.com/articles/s41467-022-29440-z
 
This is the first study to utilize infected non-human primates (NHPs) to understand the neurological symptoms associated with SARS-CoV-2 infections and "long COVID."
 
To date, many patients with COVID-19 report neurological symptoms. Severe COVID-19 can affect the brain and manifest as stroke, meningoencephalitis, and hemorrhagic necrotizing encephalopathies. Mild symptoms like dizziness or headache can be a part of the neuropathology associated with the disease. However, the origin and development of COVID-19 affecting the nervous system are unclear.
 
The study team used two NHPs, the Rhesus macaques (RM) and African green monkeys (AGMs), as SARS-CoV-2 infection models to assess brain pathology.
Brain inflammation
 
In all, four RMs and four AGMs were infected with SARS-CoV-2, 2019-nCoV/USA-WA1/2020 strain, a near-wildtype strain. Two RMs and two AGMs were infected via an aerosol challenge, and two RMs and two AGMs were infected via multiple mucosal routes. In addition, two RMs and two AGMs were controls that were mock-infected with growth med ia. All exposed animals developed an infection within the first week of exposure, irrespective of the infection method.
 
During the course of the study, two AGMs had to be euthanized because they manifested severe symptoms.
 
Neuroinflammation and Neuronal Degeneration
 
The study showed that brain inflammation was observed in all animals, but it was more significant in SARS-CoV-2 infected animals.
 
The study team also observed significant changes in neuronal morphology. Neuronal degeneration was observed. To identify the mechanism of degeneration, the brain regions were assessed for the presence of cleaved caspase 3, a marker for programmed cell death or apoptosis.
 
It was found that except for one AGM, all infected animals had cleaved caspase 3 positive cells in at least one region of the central nervous system (CNS). One RM and two AGMs had cleaved caspase 3 positive cells in more than one brain region. One RM had cleaved caspase 3 positive cells in all brain regions. The mock-infected animals had a few or no cleaved caspase 3 positive cells in the brain.

One AGM that was euthanized did not show caspase 3 positive cells in the CNS. This suggests that apoptosis in the CNS may occur in the later stages of the disease.
 
Microbleeds In Brain Tissue
 
The research findings showed microhemorrhages or microbleeds in the brain tissue of the all animals but the infected animals had larger bleeds. Infected animals had a higher number of microbleeds.
 
Typically, microhemorrhages occur with aging, possibly due to an age-related decline in elasticity of the blood vessels and an increase in blood pressure. These microbleeds can promote blood clotting that can stop the bleed but they can also cause a stroke. The presence of clots was examined by an accumulation of CD61.
 
The examination revealed that multiple blood vessels were CD61 positive in all animals, irrespective of microbleeds. More clots were observed in infected animals. Thus, during SARS-CoV-2 infection leakage of blood vessels without injury occurs more frequently.
 
Brain Hypoxia
 
Typically, the brain has a high energy demand. It requires oxygen and glucose. A reduction in blood flow causes a decrease in oxygen and glucose that can affect neuronal vitality and cause neurotoxicity and inflammation.
 
It was found in one AGM that was euthanized, several microbleeds in the brain that may have been the reason for the animal's rapid decline. Possibly, the AGM's lung deterioration contributed to the microbleeds. This needs to be investigated further.
 
Interestingly, all infected animals had SpO2 levels between 89 and 99%. The SpO2 levels were mostly below 95% for most infected animals over the study course.
 
Although these low blood oxygen levels (hypoxia) are not alarming,they reflect impaired gas exchange in the lungs.
 
In most cases, minor declines in oxygen levels may promote neuronal injury. Cells that are vulnerable to hypoxia and nearby cells were degenerate or undergoing apoptosis. Hypoxia was assessed by staining the oxygen-regulated alpha subunit of hypoxia-inducible factor-1 (HIF-1a). The regions of the brain that showed the most significant injury were assessed for hypoxia. Compared to mock-infected controls, the brains of infected animals showed higher HIF-1a levels.
 
Presence Of SARS-CoV-2
 
The study team notes that the brain pathology that is observed in this study could be due to SARS-CoV-2 infecting the brain cells or an indirect consequence of the disease.
 
Viral presence in the brain samples was assessed by staining for the viral nucleocapsid protein or in situ hybridization. Staining showed rare SARS-CoV-2 infection in the brain, which appeared to be restricted to the blood vessels. In situ hybridization also showed viral presence in the brains of infected animals. Viral infection was observed in the brain-associated endothelial cells in deep brain structures. Viral presence was observed even in the absence of severe disease or obvious neurological symptoms.
 
The stud team concluded that NHPs can act as a viable model for addressing SARS-CoV-2-associated neuropathology. Conclusions drawn from this model can be translated to human disease.
 
The study findings alarmingly revealed that neuroinflammation, microhemorrhages, brain hypoxia, neuronal degeneration, and apoptosis are observed in SARS-CoV-2 infected NHPs.
 
Importantly, neuropathology is observed in infected animals that do not manifest severe respiratory symptoms.
 
Also, despite rare viral presence detected in brain endothelial cells, it does not correlate with the severity of brain injury.
The study findings strongly suggest that long COVID patients need a long-term neurological follow-up.
 
Researchers also need to pay attention to excess deaths as a result of brain clots and strokes and also other brain related developments including brain cancer and tumors and various other aggressive neurodegenerative diseases.
 
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