Targeting pathogenic innate lymphoid cells in airway disease

Analysis of 75,770 military personnel from 2001 to 2013 in the Millennium Cohort Study found that up to 5% developed new-onset asthma and combat exposure increased the risk by 24-30%. Specifically, deployment to Iraq and Afghanistan, which represents the largest cohort of current Veterans (VetPop 2016), significantly increased the risk of new-onset asthma with an incidence of up to 14%. In recent studies, new onset asthma was diagnosed in 31-52% of soldiers with post deployment respiratory complaints at the War Related Illness and Injury Study Center (WRIISC). Deployed Veterans to the Middle East are at increased risk of developing new onset asthma compared with control non-deployed soldiers and most base-deployed personnel (>85%) have been exposed to burn pits which are implicated in asthma and other chronic lung diseases. Areas around burn pits emit elevated levels of fine particulate matter (PM), polyaromatic hydrocarbons (PAH), and dioxins though limited data exists regarding how these burn pit components may induce aberrant airway immune responses. In this proposal, we will test how lung innate lymphoid cells (ILCs) promote asthma features in WT C57B/6 mice after intranasal challenges with combinations of BaP (PAH), TCDD (dioxin), and PM with and without a fungal allergen present in Middle East dust storms (Alternaria alternata). We will analyze mice for levels of airway inflammation, mucus production, and airway hyperresponsiveness (by invasive PFT). ILC endpoints assessed by flow cytometry include intracellular cytokine production, proliferation, and with single-cell RNA-sequencing. We will test whether ILC activation in the burn pit-relevant model can be suppressed by targeting the intracellular protein STING and whether STING regulates ILC inhibition through RNA binding protein RBM3. In translational studies, we will perform in vitro human ILC assays with burn pit-relevant components and assess ILC changes with STING activation. Finally, we have assembled co-investigator team with Million Veteran Program (MVP) genomic expertise (Dr. Nievergelt VA San Diego) and propose to assess ILC gene and high-risk asthma SNP association with Veteran asthma in the MVP database. Given our robust preliminary data, we expect to find that ILCs promote asthma features in the burn pit model and targeting STING can suppress ILC responses and lung inflammation, in part through RBM3. We also expect these findings to translate to human ILC responses and that ILC-related SNPs will link with Veteran asthma.