Defining the neuroinvasive potential of SARS-CoV-2 in brain autopsies of COVID-19 patients and controls

Project Lead: Dr Emily Happy Miller, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center-New York Presbyterian Hospital

Awarded: 2020

Throughout my training I have been interested in how viruses affect their hosts. After receiving my PhD training in virology, I came to Columbia University Irving Medical Center to complete my Internal Medicine and Infectious Disease residency and fellowship training. New York City became the epicenter of the COVID-19 pandemic in the United States in Spring 2020. During this time, I helped care for patients with many different COVID-19 manifestations, including encephalopathy. I became involved with a number of research projects, including studies to better understand neurological manifestations of COVID-19. Currently, it is unclear whether the neurological manifestations are a consequence of direct infection of the CNS by the virus or due to secondary sequelae from the virus-induced systemic inflammatory response. We have one of the largest local populations of COVID-19 patients and one of the largest collections of brain autopsies of COVID-19 patients. Analysis of the brain tissue for the virus is essential to understand whether SARS-CoV-2 affects the brain directly or indirectly. We will utilize this large collection of brain autopsy samples to determine the presence of SARS-CoV-2 in the brain by quantitative reverse transcription-PCR and viral RNA staining.  Our study will elucidate possible routes of CNS infection by the virus and identify brain regions and cell types most vulnerable to either direct infection or the effects of systemic cytokines. This seed funding from the Encephalitis Society will provide valuable support for this work in understanding the role of the virus in the brain of people who died from COVID-19. We hope that this work will help shed light on how the virus may be contributing to neurological findings in patients who are alive and dealing with COVID-19 disease. This information will be critical for thoughtful design of diagnostic tools to treat neurological complications from COVID-19 and understanding the long-term effects of the virus on the CNS

This seed funding has now been completed. Please see below a summary of the research findings

"Neurological signs and symptoms are known to occur in COVID-19 disease.  Some of these symptoms, such as brain fog, headache and depression can linger for months.  It has been largely unknown if the neurological findings are due to infection of the brain with SARS-CoV-2.   Over the past several months, our group completed a large study on COVID-19 neuropathology in brain autopsies at our institution.  This multidisciplinary study involving Neuropathology, Neurology, Infectious Diseases, and Neuroradiology was recently published in the journal Brain (Thakur et al, Brain,  In the study we presented clinical, neuropathological and molecular findings from autopsies of 41 predominately Hispanic/latinx patients who died with COVID-19.  Neuropathological examination revealed hypoxic/ischemic changes in all brains as well as microglial activation.  Both hypoxic changes and microglial activation can lead to permanent neuronal loss. While we found damage in the brains of these patients, we did not find significant viral infection in the brain tissue.  Quantitative reverse-transcriptase PCR found low but detectable viral RNA in the majority of brains.  However, this was far lower than what was found in nasal passageway tissue.  Viral RNA did not correlate with the histopathological alterations seen, suggesting it is unlikely that viral infection is responsible for these changes.  Immunocytochemical staining for viral antigens and RNA in situ hybridization for viral genomic material did not find either in brain tissue, suggesting that the low RT-PCR values might have reflected viral RNA in blood vessels or leptomeninges.  Future studies are needed to see if these pathological findings, which may also be present in COVID-19 survivors, contribute to any of the chronic neurological problems reported by patients. "

Dr Emily Miller

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