It is known that respiratory viral infection in infancy cause asthma. But the detailed mechanisms underlying the induction of allergic inflammation by virus infection are is not fully understood. Many papers have shown that, not only pathogen-derived factors such as virus DNA and RNA, factors released from dying or stressed cells, damage-associated molecular patterns (DAMPs), are recognized by immune cells and contribute to inflammation. Interestingly, host DNA as a DAMP is known to induce type 2 immune responses and exacerbates allergic inflammation. Host DNA is recognized by intracellular DNA sensors and activates cyclic GMA-AMP synthase (cGAS). Then activated cGAS generates cyclic GMP-AMP(cGAMP) as a second messenger. We hypothesized that host DNA release from damaged cells by virus participates in allergic inflammation via the action of cGAMP. In this study, we investigated the effect of cGAMP on the onset of asthma.
House dust mite antigen (HDM) was administered intranasally to C57B/6J mice with or without cGAMP as an adjuvant, and then mice were challenged with intranasal administration of house dust mite antigen (HDM) on days 7, 9, 11, and 13. Twenty-four hours after last challenge, we collected blood, BALF, lungs. Serum antibodies were measured by ELISA, and cells in BALF were analyzed by FACS. We performed similar experiment using gene-knockout mice to evaluate the factors involved in this inflammation model.
The number of eosinophils in BALF was significantly increased in mice sensitized by HDM with cGAMP. Histological analysis revealed that infiltration of inflammatory cells and mucus-containing goblet cells in the lung were also increased after the sensitization of HDM with cGAMP. Moreover cGAMP-adjuvanted HDM led to airway hyper-responsiveness. These effects were dependent on STING/TBK1, that are downstream factors of cGAMP signaling pathway.
cGAMP acts an adjuvant and induces allergic inflammation in the lung. These results suggest that cGAMP may be involved in viral infection-induced asthma through the release of DAMPs.