The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires’ disease in humans

<div><p>The cyclic GMP-AMP synthase (cGAS)-STING pathway is central for innate immune sensing of various bacterial, viral and protozoal infections. Recent studies identified the common HAQ and R232H alleles of <i>TMEM173/STING</i>, but the functional consequences of these variants for primary infections are unknown. Here we demonstrate that cGAS- and STING-deficient murine macrophages as well as human cells of individuals carrying HAQ <i>TMEM173/STING</i> were severely impaired in producing type I IFNs and pro-inflammatory cytokines in response to <i>Legionella pneumophila</i>, bacterial DNA or cyclic dinucleotides (CDNs). In contrast, R232H attenuated cytokine production only following stimulation with bacterial CDN, but not in response to <i>L</i>. <i>pneumophila</i> or DNA. In a mouse model of Legionnaires’ disease, cGAS- and STING-deficient animals exhibited higher bacterial loads as compared to wild-type mice. Moreover, the haplotype frequency of HAQ <i>TMEM173/STING</i>, but not of R232H <i>TMEM173/STING</i>, was increased in two independent cohorts of human Legionnaires’ disease patients as compared to healthy controls. Our study reveals that the cGAS-STING cascade contributes to antibacterial defense against <i>L</i>. <i>pneumophila</i> in mice and men, and provides important insight into how the common HAQ <i>TMEM173/STING</i> variant affects antimicrobial immune responses and susceptibility to infection.</p><p>Trial registration</p><p> <a href="" target="_blank">DRKS00005274</a>, German Clinical Trials Register</p></div>