SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19
Geidy E. Serrano, Jessica E. Walker, Cécilia Tremblay, Ignazio S. Piras, Matthew J. Huentelman, Christine M. Belden, Danielle Goldfarb, David Shprecher, Alireza Atri, Charles H. Adler, Holly A. Shill, Erika Driver‐Dunckley, Shyamal H. Mehta, Richard J. Caselli, Bryan K. Woodruff, Chadwick F. Haarer, Thomas Ruhlen, Marı́a José Torres, Steve Nguyen, Dasan Schmitt, Steven Z. Rapscak, Christian Bime, Joseph L. Peters, Ellie Alevritis, Richard Arce, Michael J. Glass, Daisy Vargas, Lucia I. Sue, Anthony J. Intorcia, Courtney M. Nelson, Javon Oliver, Aryck Russell, Katsuko E. Suszczewicz, Claryssa I. Borja, Madison P. Cline, Spencer J Hemmingsen, Sanaria H. Qiji, Holly M Hobgood, Joseph P. Mizgerd, Malaya K. Sahoo, Haiyu Zhang, Daniel Solis, Thomas J. Montine, Gerald J. Berry, Eric M. Reiman, Katharina Röltgen, Scott D. Boyd, Benjamin A. Pinsky, James L. Zehnder, Pierre J. Talbot, Marc Desforges, Michael DeTure, Dennis W. Dickson, Thomas G. Beach
Abstract
Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.