Defining viral-host mechanisms of neuroinflammation after human metapneumovirus infection 2257071

Abstract

Abstract Introduction Human metapneumovirus (hMPV) is a leading cause of severe respiratory illness in infants, and can lead to the rare development of acute neurological complications such as encephalitis and seizures. Severe early-life viral infections with hMPV, RSV and other respiratory viruses have been linked to long-term neurodevelopmental impairments, including cognitive, motor, and behavioral deficits. However, the viral-host mechanisms driving neurotropism and neuroinflammation associated with these clinical outcomes remain poorly understood. Methods Here, we have modeled HMPV-infection of the central nervous system (CNS) using human primary neuronal culture, human brain organoid models and in vivo mouse models of intranasal HMPV infection. In these models we used proteomics, single-cell genomics and functional studies to determine the mechanisms of neuroinflammation driven by HMPV infection. We then utilized a high-throughput small-molecule drug screen to identify novel inhibitors of HMPV infection. Results We demonstrated that hMPV can directly infect and replicate within neuronal and nonneuronal cells in the CNS leading to activation of proinflammatory innate immune responses and markers of neuronal damage using human cell and organoid models. Moreover, we identified different signatures of HMPV innate immune activation compared to a related respiratory virus, RSV. In a mouse model, we found that after Intranasal hMPV infection, virus was detected in both lung and brain tissues with inflammatory signatures. Finally, we performed a drug repurposing screen to identify novel antiviral drugs that could be used to block HMPV infection of both respiratory and CNS tissues. Conclusion These findings establish HMPV as a virus capable of CNS infection and inflammation, identify me mechanisms of host-virus immune interactions and identified novel antiviral drugs that could be used as therapies to mitigate both respiratory and neurological complications associated with HMPV infection. Funding Source Paul Henson Endowment, Children’s Mercy Kansas City Topic Categories Viral Immunology (VIR)