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Inflammation and Hypoxia May Underlie Neuronal Death in Brain of SARS‐CoV‐2 Infected Non‐Human Primates
Author(s) -
Mayer Meredith,
Rutkai Ibolya,
Hellmers Linh,
Ning Bo,
Huang Zhen,
Monjure Christopher,
Maness Nicholas J.,
RussellLodrigue Kasi,
Hu Tony Y.,
Roy Chad,
Blair Robert,
Bohm Rudolf,
DoyleMeyers Lara,
Rappaport Jay,
Fischer Tracy
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r5173
Subject(s) - pathology , neuroinflammation , microglia , gliosis , hypoxia (environmental) , cerebellum , human brain , biology , brainstem , neuropathology , immunohistochemistry , h&e stain , medicine , inflammation , neuroscience , immunology , disease , chemistry , organic chemistry , oxygen
Neuropathological complications are frequently observed in SARS‐CoV‐2 infection and brain autopsies from human subjects who died from COVID‐19 have revealed significant pathology, including wide‐spread neuroinflammation, hypoxic‐ischemic injury, and microhemorrhages. To begin to understand the neuropathogenesis of SARS‐CoV‐2 infection, we investigated brain from infected non‐human primates (NHP)s for pathological changes consistent with that seen among humans. Eight aged NHPs were inoculated with the 2019‐nCoV/USA‐WA1/2020 strain of SARS‐CoV‐2 via a multi‐route mucosal or aerosol challenge. Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining was done on seven brain regions to elucidate general pathology, microhemorrhages, platelet derived thrombi, neuronal apoptosis, microglia and astrocyte morphology, hypoxia, and virus present. Similar to humans, pathology was variable but included wide‐spread neuroinflammation, nodular lesions, neuronal degeneration, and microhemorrhages. Neuronal degeneration was most often seen in the cerebellum and brainstem of infected animals. Neuronal death was confirmed through FluorJade C and cleaved (active) caspase 3 IHC, which showed foci of positivity, particularly among Purkinje cells of the cerebellum. Importantly, this was seen among infected animals that did not develop severe respiratory disease. Hypoxia inducible factor‐1α (HIF‐1α) was observed at a higher intensity around the vasculature within deep brain regions of the infected animals. Microhemorrhages were prevalent among all animals but were less frequently associated with platelet derived thrombi in the infected animals, as compared to mock‐infected controls. Sparse virus was detected in brain endothelial cells but did not associate with the severity of CNS injury. Increased HIF‐1α suggests that brain hypoxia may promote neuronal degeneration within infected brain. Wide‐spread neuroinflammation may also contribute to neuronal injury/death and neurological manifestations seen in the context of infection.