Mast Cell Immune Responses to Primary Infection With Human Rhinovirus A16 Are Differentially Regulated by the Airway Epithelium

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2024.209.1_MeetingAbstracts.A6987

CONTROL OF AIRWAY INFLAMMATION AND IMMUNE RESPONSE IN ASTHMA / Poster Discussion Session / Wednesday, May 22/08:15 AM-10:15 AM / San Diego Convention Center, Room 31A-C (Upper Level)

R. C. Murphy, M. Liu, Y. Lai, D. Grosvenor, M. W. Czarnecki, W. A. Altemeier, J. S. Debley, M. C. Altman, T. S. Hallstrand

Rationale: Human rhinoviruses (RVs) are common triggers for asthma exacerbations and have been implicated in asthma development but the relationship between RV infection and type-2 (T2) airway inflammation remains incompletely understood. Our laboratory and others have identified a distinct population of mast cells (MCs) located in the airway epithelium (“intraepithelial MCs”), which are correlated with airway hyperresponsiveness and T2 and non-T2 mediators of inflammation (Murphy RC AJRCCM 2023). We have previously demonstrated that there is considerable crosstalk between airway epithelial cells (AECs) and MCs that modulates epithelial responses to RV infection (Murphy RC JACI 2023). More recently, we have shown that RV16 infection of MCs leads to IL13 expression and is regulated through autocrine signaling mechanisms, including several epithelial-associated mediators (Lai Y AJRCCM 2022;205:A3745). Here we examine how MC immune responses following RV16 are

differentially regulated by the epithelium. Methods: Laboratory of allergic disease-2 (LAD2) MCs were infected with RV16 for 4 hours and added to the basolateral compartment of a coculture system with primary AECs obtained from healthy adult donors, which were fully differentiated at air-liquid interface. MC and AEC gene expression were examined by qPCR and bulk RNA-sequencing (RNA-seq) at multiple timepoints. Results: There was a marked and sustained induction of IL13 expression in MCs at 24 and 48 hours following RV16 infection, which was attenuated in MCs cocultured with AECs (Figure 1A). However, the presence of AECs resulted in relatively enhanced MC IFNB1 expression at 24 hours (Figure 1B). AECs promoted sustained expression of key inflammatory cell surface receptors on MCs following RV16 infection, including IL1RL1, IL18R1, and CCR5 (Figure 1C). Conclusion: RV16 infection of MCs results in bidirectional crosstalk between AECs and MCs that attenuates the T2 response and accentuates the antiviral response by MCs. This crosstalk further modulates key receptors on MCs that are implicated in asthma progression. These results highlight the role of intraepithelial MCs in modulating airway inflammation and provide key insights into the mechanisms responsible for viral-induced exacerbations and asthma pathogenesis.

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