The sins of first exposure: simultaneous allergen- and influenza-mediated signaling results in mast cell hyperactivity

Abstract Each year hundreds of thousands of individuals in United States are hospitalized due to influenza A virus infection (IAV). Asthma is one of the leading co-morbidities among these hospitalized patients. Given the detrimental role mast cells can play during both asthma and IAV infection, we hypothesized simultaneous stimulation of mast cells by allergens and IAV may contribute to the asthmatic exacerbations often accompanying IAV infection. Here we show that signaling by both FcɛRI cross-linking and IAV infection (A/WSN/33 or A/PR/8/34) results in a heightened release of proinflammatory cytokines by these cells in vitro. At the same time, the type I interferon response is suppressed. As early as 1.5 hours post infection Ptgs2 mRNA is upregulated. Furthermore, chemical inhibition of COX-2 or mPGES-1 reduces this heightened proinflammatory response, suggesting a role for prostaglandin E2 in the mast cell hyperactivity. The addition of exogenous prostaglandin E2 can partially mimic this phenotype, though not as drastically as cells infected with IAV, suggesting there is an as yet unidentified viral component contributing to the mast cell hyperactivity. Surprisingly active viral replication is not necessary, as UV-inactivated IAV is capable of inducing mast cell hyperactivity as strongly as untreated virus. Interestingly, within 24–48 hours, infected mast cells die irrespective of FcɛRI stimulation. Taken together, our data suggest that IAV may incite asthmatic exacerbation through enhanced cytokine and prostaglandin production from mast cells receiving two distinct stimuli simultaneously, but ultimately mast cell death induced by IAV infection limits the duration of the asthmatic exacerbation.