Identification of the cellular mechanisms of neurological inflammation after RSV infection using a human brain organoid model 3139

Abstract Description Respiratory syncytial virus (RSV) is a major cause of severe respiratory illness. While most symptoms of RSV infection are linked to airway inflammation, emerging clinical data reveals that RSV can infiltrate the central nervous system (CNS), and lead to neurological manifestations such as seizures and central apnea, and in rare cases, encephalopathy, that can have long-term neurodevelopmental consequences. Despite detection of viral infection in the CNS, the pathophysiological mechanisms of RSV-mediated CNS disease are not well defined. Here, we have modeled RSV-infection of the CNS using human primary neuronal cultures and human brain organoid models of infection. Using confocal microscopy, biochemical and single-cell genomics approaches, we have identified that RSV could productively infect neurons, caused cell death and inflammatory responses, and altered the overall transcriptome of neurons and non-neuronal CNS cell populations after infection. Moreover, we have identified key cell-surface adhesion molecules that are critical for RSV infection in the CNS, and optimized soluble forms of these cell-surface glycoproteins to block viral infection. Our findings advance our understanding of RSV dissemination into the CNS and highlight a potential soluble receptor-based therapy to mitigate against lung and CNS inflammation. This work paves the way for new therapeutic strategies against RSV, and establishes an approach for characterizing viral infection in the human CNS. Funding Sources Supported by Children’s Mercy Research Partners, Children’s Mercy Research Institute and Paul Henson Endowment Clinical Scholar Award. Topic Categories Viral Immunology (VIR)