Establishing Mechanisms by which Viral Infection Exacerbates Asthma 2258608

Abstract Introduction Asthma exacerbations result in accelerated airway remodeling, increased airway obstruction, and significant loss of lung function – respiratory viruses account for approximately 80% of exacerbations. Previous studies of viral exacerbation have reported both amplification of type-II inflammation and repression of the antiviral response. However, the mechanism by which the type-II milieu is potentiated upon viral infection of an asthmatic lung has not been defined. Methods To identify the immune cell subsets responsible for driving viral exacerbation, we utilized a model of Influenza A/PR/8/34 (IAV) infection in C57BL/6 mice chronically sensitized with house dust mite (HDM). Results We confirmed that viral infection can result in recruitment of eosinophils and expansion of cDC2, ILC2, and activated CD4 T cells. In addition, our study showed viral exacerbation increased the proportion of activated eosinophils found in the lung. ILC2s in viral exacerbation have both increased ST2 expression and upregulation of MHCII. At the height of the innate response, HDM sensitized mice experiencing an IAV-induced exacerbation exhibited similar airway hyperresponsiveness to mice experiencing an allergic exacerbation during a methacholine challenge. A characterization of the CD4 T cell compartment revealed that a population of activated GATA3+CD4 T cells expands following viral exacerbation and remains throughout the remainder of the infection, suggesting that virally induced Th2 cells may be playing a role in this pathology. Interestingly, our study also shows a subpopulation of GATA3+ Tregs expands in the lung-draining mediastinal lymph node following IAV exacerbation of HDM-sensitized lungs. Conclusion Our data confirms the previous published work that viral infection can exacerbate asthma, identifies Th2s and GATA3+Tregs as CD4 T cell subsets of interest, and provides additional evidence for other innate immune cell types within the asthmatic lung that may drive the type-II response in viral exacerbation. Funding Source Viola Vestal Coulter Foundation Award, Murnick Asthma Accelerator Award, AHA Pre-Doctoral Fellowship 25PRE1368833 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)