432.12 - Inflammation and Hypoxia May Underlie Neuronal Death in Brain of SARS-CoV-2 Infected Non-Human Primates

Meredith Mayer (Tulane National Primate Research Center), Ibolya Rutkai (Tulane University School of Medicine), Linh Hellmers (Tulane National Primate Research Center), Bo Ning (Tulane University School of Medicine), Zhen Huang (Tulane University School of Medicine), Christopher Monjure (Tulane National Primate Research Center), Nicholas Maness (Tulane National Primate Research Center), Kasi Russell-Lodrigue (Tulane National Primate Research Center), Tony Hu (Tulane University School of Medicine), Chad Roy (Tulane National Primate Research Center), Robert Blair (Tulane National Primate Research Center), Rudolf Bohm (Tulane National Primate Research Center), Lara Doyle-Meyers (Tulane National Primate Research Center), Jay Rappaport (Tulane National Primate Research Center), Tracy Fischer (Tulane National Primate Research Center)

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 (Hamp;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.

P51OD011104; Emergent Ventures at the Mercatus Center, George Mason University Fast Grants for COVID-19