SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19

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.

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

“…Perivascular cuffing (Fig. 3b) is well described in histological examinations of brains from deceased COVID-19 patients 38,39,56,87,88 . Other lesions observed in the BA.5-infected K18-hACE2 mouse brains, that have also been described in post-mortem COVID-19 patients, include perivascular edema (Fig.…”

“…Infection of K18-hACE2 mice with original ancestral isolates via intranasal inoculation, usually results in fulminant and lethal brain infections, with virus likely entering the brain via the olfactory epithelium, across the cribriform plate and into the olfactory bulb [49][50][51][52][53][54] . This route of entry into the brain may also be relevant for COVID-19 patients 35,38,39,[55][56][57] .…”

“…The mechanism(s) whereby brain pathology/immunopathology and/or neuropathology might manifest in COVID-19 patients remains debatable, with the systemic cytokine storm and/or direct brain infection likely involved 22,[27][28][29][30][31][32] . A number of studies have now shown brain infection in COVID-19 patients [33][34][35][36][37] , with viral RNA or protein detected in the brains of 20-38% of patients that died of COVID-19 38,39 . A number of groups have also reported detection of viral RNA in cerebrospinal fluid of COVID-19 patients [40][41][42][43][44] , including patients infected with omicron virus 45 .…”

Sensitivity of diffusion-tensor and correlated diffusion imaging to white-matter microstructural abnormalities: application in COVID-19

“…The strong anterior emphasis of these effects may be traced back to the role of the olfactory bulb (OB) as the most likely entry point for SARS-CoV-2 in the brain (Serrano et al, 2022; Xydakis et al, 2021). The OB has been shown to be the most likely brain region to contain SARS-CoV-2 and shows significant changes in gene expression in COVID-19 (Serrano et al, 2022).…”

“…The strong anterior emphasis of these effects may be traced back to the role of the olfactory bulb (OB) as the most likely entry point for SARS-CoV-2 in the brain (Serrano et al, 2022; Xydakis et al, 2021). The OB has been shown to be the most likely brain region to contain SARS-CoV-2 and shows significant changes in gene expression in COVID-19 (Serrano et al, 2022). Moreover, studies examining the brain vasculature in deceased COVID-19 patients showed strong fibrinogen staining in the OB, indicating a leaky blood-brain barrier (BBB) at autopsy (Lee et al, 2022).…”