Tissue resident memory cells formed after neonatal viral infection contribute to asthma 2255698

Abstract

Viral lower respiratory tract infections are remarkably common amongst children less than 5 years old. Human metapneumovirus (HMPV) is one leading cause of these infections in children under 5 years old. Additionally, infants diagnosed with HMPV bronchiolitis are at a four-fold increased risk of developing asthma. The mechanisms by which early-life HMPV infection influences long-term immune responses remain poorly understood. To model this clinical phenomenon, neonatal or adult mice were infected with HMPV, then re-challenged 6 weeks later. We assessed mucus, airway reactivity, eosinophil recruitment, and T cell subset phenotypes. FTY720 and anti-CD4 were used to modulate TRM populations. Treatment with fedratinib, a Jak2-selective, was performed on the first 3 days of rechallenge via oral gavage. We demonstrated that neonatal mice re-challenged with HMPV as adults mount a robust Th2 response consistent with asthma pathology (e.g. eosinophil recruitment, mucus production, and airway hyperreactivity). Mice initially infected with HMPV as adults followed by HMPV re-challenge showed no signs of Th2 inflammation. The tissue resident memory compartment (TRMs) also showed evidence of Th2-skewing following neonatal, but not adult, HMPV infection. Mice treated with FTY720, an inhibitor of lymphocyte trafficking, had a robust Th2 response in the neonatal/adult rechallenge model. Local and systemic depletion of CD4+ T cells mitigated this response. Further, this subset of enriched Th2 TRMs following neonatal HMPV had a unique transcriptional profile, including differential expression Jak2. Mice treated with fedratinib showed reduced eosinophil recruitment, Th2 cytokine production, and mucus hypersecretion compared to vehicle controls. Collectively, these studies identify a targetable Th2 TRM population following early life infection that can contribute to asthma-like inflammation following re-exposure to a viral pathogen. The AAAAI Foundation Faculty Development Award and NIAID Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)