학술논문
SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19
ORIGINAL ARTICLE
ORIGINAL ARTICLE
Document Type
Report
Author
Serrano, Geidy E.; Walker, Jessica E.; Tremblay, Cecilia; Piras, Ignazio S.; Huentelman, Matthew J.; Belden, Christine M.; Goldfarb, Danielle; Shprecher, David; Atri, Alireza; Adler, Charles H.; Shill, Holly A.; Driver-Dunckley, Erika; Mehta, Shyamal H.; Caselli, Richard; Woodruff, Bryan K.; Haarer, Chadwick F.; Ruhlen, Thomas; Torres, Maria; Nguyen, Steve; Schmitt, Dasan; Rapscak, Steven Z.; Bime, Christian; Peters, Joseph L.; Alevritis, Ellie; Arce, Richard A.; Glass, Michael J.; Vargas, Daisy; Sue, Lucia I.; Intorcia, Anthony J.; Nelson, Courtney M.; Oliver, Javon; Russell, Aryck; Suszczewicz, Katsuko E.; Borja, Claryssa I.; Cline, Madison P.; Hemmingsen, Spencer J.; Qiji, Sanaria; Hobgood, Holly M.; Mizgerd, Joseph P.; Sahoo, Malaya K.; Zhang, Haiyu; Solis, Daniel; Montine, Thomas J.; Berry, Gerald J.; Reiman, Eric M.; Roltgen, Katharina; Boyd, Scott D.; Pinsky, Benjamin A.; Zehnder, James L.; Talbot, Pierre; Desforges, Marc; Deture, Michael; Dickson, Dennis W.; Beach, Thomas G.
Source
Journal of Neuropathology and Experimental Neurology. September 2022, Vol. 81 Issue 9, p666, 30 p.
Subject
Language
English
ISSN
0022-3069
Abstract
INTRODUCTION The coronavirus SARS-CoV-2 is primarily associated with severe respiratory disease, termed COVID-19, but there have been numerous reports of an accompanying broad range of neurological signs, symptoms, and syndromes, [...]
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. Key Words: Amygdala, Cytokine, Deafferentation, Encephalitis, Microglia, Olfactory bulb, SARS-Cov-2.
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. Key Words: Amygdala, Cytokine, Deafferentation, Encephalitis, Microglia, Olfactory bulb, SARS-Cov-2.