Abstract: The neurological manifestations of SARS-CoV-2 infection, known as neuroCOVID-19, have raised concerns regarding the underlying mechanisms and potential involvement of antibodies. Antibodies can exert inflammatory or anti-inflammatory responses based on their glycosylation patterns. Building upon our data, our central hypothesis is that inflammatory IgGs associated with SARS-CoV-2 infection trigger activation and/or damage to resident brain cells and endothelial cells, leading to disruptions in brain homeostasis. Furthermore, we propose that these inflammatory IgGs exhibit an enrichment for autoreactivity against brain antigens. To test this hypothesis, in Aim 1, we will elucidate the impact of inflammatory IgGs on glial cells, neurons, and endothelial cells. By utilizing well-characterized inflammatory and anti-inflammatory IgGs obtained from plasma and CSF of COVID-19 donors, we will assess their effects on human induced pluripotent stemcell (iPSC)-derived astrocytes, microglia, neurons, and brain endothelial cells. This investigation will evaluate changes in cellular phenotype, inflammatory status, and functional integrity. In Aim 2, we will investigate the potential role of inflammatory IgGs in brain homeostasis using chimeric human brain/mouse NSG mice. Through the infusion of labeled inflammatory and anti-inflammatory IgGs, we will examine their trafficking into the brain, characterize their cellular associations, and determine their impact on brain homeostasis. In Aim 3, we will determine the involvement of inflammatory IgGs in COVID-19 autoreactive responses. Previous studies have indicated the presence of autoreactive antibodies in COVID-19, with some reports linking them to neuroCOVID-19. However, a comprehensive understanding of the impact of autoreactive IgGs in the context of COVID-19, particularly their brain antigen targets, remains unclear. To address this, we will employ Omics-scale high density protein microarrays to discover COVID-19 autoreactive antibodies in the brain. Subsequently, we will assess their effects on resident brain cells and investigate the contribution of inflammatory IgGs to t his autoreactive phenotype, including analysis of their glycosylation patterns. Collectively these studies will provide valuable insights into the mechanisms underlying the neurological effects of COVID-19 and the role of antibodies in these processes. The outcomes of this research have the potential to inform therapeutic interventions targeting the neurological complications associated with SARS-CoV-2 infection.

Narrative: We are studying the neurological effects of COVID-19, also known as neuroCOVID-19. We are particularly interested in the role of antibodies in these effects. We believe that inflammatory antibodies associated with the SARS-CoV-2 virus can cause damage to the cells in our brains and disrupt their normal functioning. These inflammatory antibodies may also have a special affinity for targeting brain cells. Through laboratory experiments and animal models, we aim to understand the role of these antibodies in neuroCOVID-19. This research has implications for developing targeted therapies for COVID-19-related neurological complications