NeuroCovid

Wider research context / theoretical framework

The pandemic of coronavirus disease 19 (COVID-19) marks the emergence of the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been associated with significant global morbidity and mortality. Recently, there has been increasing recognition of neurologic symptoms in COVID-19 patients. The pathophysiology underlying the encephalopathy induced by SARS-CoV-2 is yet to be elucidated.

Hypotheses / research questions / objectives

Analysis of the limited COVID-19 literature favors the hypothesis that SARS-CoV-2 might trigger an immune-mediated encephalopathy. Based on previous findings and our preliminary data, we hypothesise that upon SARS-CoV-2 infection, the immune system generates anti-spike antibodies. These antibodies may recognize and attack neurological autoantigens due to molecular mimicry. The research question of this project is: is auto-immunity responsible for the Neurocovid pathological manifestation? We aim at obtaining a detailed clinical characterization of Neurocovid patients, identifying the endogenous target(s) recognized by Neurocovid CSF autoantibodies, and scrutinizing the mechanism underlying Neurocovid pathological manifestation.

Approach / methods

We will analyse well characterised human Neurocovid samples (CSF and serum) for the presence of neurologically relevant auto-antibodies and pro-inflammatory cytokines. We will identify potential novel antigens exploiting a state-of-art forward genetic screen that combine GeCKO library and FACS. We will validate the targets using live cell-based assays, including immunofluorescence or flow cytometry. We will investigate the molecular mechanisms underlying Covid19-related neurophysiological dysfunctions in disease-relevant neuronal models, such as rodent primary neuronal cultures and human neurons derived from induced pluripotent stem cells (iPSC). We will profile neuronal response to Neurocovid samples by electrophysiology. Ultimately, we will take advantage of a proprietary CRISPR/Cas9 human iPSC line to achieve the final validation of Neurocovid target(s).