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 Caselli, Bryan K. Woodruff, Chadwick F. Haarer, Thomas Ruhlen, Maria Torres, Steve Nguyen, Dasan SchmittSteven Z. Rapscak, Christian Bime, Joseph L. Peters, Ellie Alevritis, Richard A. 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 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 Talbot, Marc Desforges, Michael Deture, Dennis W. Dickson, Thomas G. Beach

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)666-695
Number of pages30
JournalJournal of Neuropathology and Experimental Neurology
Volume81
Issue number9
DOIs
StatePublished - Sep 1 2022

Keywords

  • Amygdala
  • Cytokine
  • Deafferentation
  • Encephalitis
  • Microglia
  • Olfactory bulb
  • SARS-Cov-2

ASJC Scopus subject areas

  • Medicine(all)

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