The susceptibility of mast cells for rhinovirus infection: implications for asthma exacerbations

Abstract

Mast cells (MCs) are classically involved in the pathogenesis of allergic asthma, however MCs also have a key role in innate immunity with an emerging role in viral immunity. During allergic asthma MCs localise in greater numbers to the bronchial epithelium which is the principal site of human rhinovirus (HRV) infection. HRVs are a major viral trigger of asthma exacerbations via mechanisms that are not completely understood. MCs are susceptible to HRV infection but their role in antiHRV responses is unknown. HRV infection of the bronchial epithelium triggers the release of the epithelial derived cytokine IL-33, which induces Th2 cytokine release from target cells with MCs being the major target of IL-33 in allergic asthma. I hypothesised that HRV infection induces MC anti-viral responses and also modulates IL-33-dependent Th2 responses in MCs.

The LAD2 human MC line and/or primary human cord blood-derived MCs (CBMCs) were infected with HRV or UV-irradiated HRV (control infection) with or without IFNβ, IFN-γ, IFN-λ or IL-33. Twenty-four hours following HRV infection, anti-viral and Th2 immune responses were assessed by RT-qPCR, MSD, ELISA and flow cytometry. Viral replication and release were determined by RT-qPCR and TCID50 assay respectively.

HRV infection induced the expression of IFN-β and IFN-λ and the induction of IFN stimulated genes (ISGs). Despite this MCs were permissive for HRV replication and the release of infectious HRV particles. This was confirmed in CBMCs. To determine the contribution of endogenous anti-viral responses, CBMCs were treated with a type I IFN receptor blocking antibody. Treatment with the blocking antibody failed to significantly increase HRV replication and release suggesting endogenous type I IFN responses were insufficient to protect MCs against HRV infection. Therefore, in order to enhance anti-viral responses, MCs were treated with exogenous IFN-β, IFNγ or IFN-λ. The induction of ISGs was enhanced by IFN-β and IFN-γ but not by IFN-λ. In addition, IFN-β treatment significantly suppressed viral replication and the release of infectious virus particles. To investigate the impact of HRV on IL-33-mediated Th2 responses, MCs were treated with IL-33 during HRV infection. IL-33 treatment induced a concentration-dependent increase in the release of IL-5 and IL13 but this was not modulated by HRV. However, IL-33 treatment increased ICAM1 expression, a receptor for HRV entry, and enhanced HRV-mediated induction of IFNβ and ISGs. This resulted in a significant increase in HRV replication but prevented significant release of infectious HRV particles.

These findings show for the first time that MCs mount anti-viral responses to HRV infection and that HRV-induced IFN-β production is enhanced by IL-33 treatment. In severe asthma, which is associated with impaired bronchial epithelial IFN responses and an increase in the localisation of MCs to the bronchial epithelium, MCs may aggravate HRV-induced exacerbations. However, IL-33 released from the epithelium may protect MCs against productive HRV infection. These findings may have important implications in HRV-induced asthmas exacerbations and the impact of novel asthma therapies particularly anti-IL-33.

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Identifiers

ORCID for Donna Davies: orcid.org/0000-0002-5117-2991

ORCID for Emily Swindle: orcid.org/0000-0003-3644-7747

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