The SARS-CoV2 respiratory beta-coronavirus causing COVID19 syndrome causes a very severe systemic comorbidities, in addition to respiratory deficits, including acute neurological manifestations and in rare cases ANE (Acute Hemorrhagic Necrotizing Encephalopathy). However, it is unclear if the virus has tropics for the CNS or whether the cytokine storm associated with the severe viral infection causes breakdown of the blood-brain barrier leading to entry of immune cells and autoantibodies into the CNS, neuroinflammation and neuronal circuitry dysfunction or death associated with neurological manifestations.
This project has the following goals:
1) Perform a systematic profiling of COVID19 patient sera to identify potential cytokines that can trigger damage to the human blood-brain barrier using an iPSC-derived human BBB model developed by Dr. Agalliu laboratory.
2) Analyze the brains of COVID19 patients obtained from the neuropathology for presence of vascular deficits such as increased hemorrhage, loss of BBB integrity, astrocyte endfeet swelling, loss of pericytes and presence of perivascular or choroid plexus immune infiltrates that would be indicative of neurovascular deficits leading to blood-brain barrier damage, impaired blood-CSF barrier and neuroinflammation.
3) Analyze the brains of COVID19 patients obtained from the neuropathology for microglia and astrocyte activation.
4) Examine the brains for the presence of the virus RNA using a recently developed FISH combined with cell-specific markers using recently developed protocols to determine its localization into the CNS (Collaboration with Robyn Klein).
5) Correlate the neurohistopathology data with clinical data for the patients.
The study will provide a better understanding of the neurotropism of the virus as well as the consequences on the neurovascular, blood-CSF barriers, neuroinflammatory and neuroimmune responses that are either a consequence of direct viral infection or indirect consequence due to the effects of the cytokine storm due to severe systemic infection.