Abstract 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 TMEM173/STING,
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 TMEM173/STING were severely
impaired in producing type I IFNs and pro-inflammatory cytokines in response
to Legionella pneumophila, bacterial DNA or cyclic dinucleotides (CDNs). In
contrast, R232H attenuated cytokine production only following stimulation with
bacterial CDN, but not in response to L. pneumophila 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 TMEM173/STING, but not of R232H TMEM173/STING, 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 L. pneumophila in mice and men, and provides
important insight into how the common HAQ TMEM173/STING variant affects
antimicrobial immune responses and susceptibility to infection. Trial
registration ClinicalTrials.gov DRKS00005274, German Clinical Trials Register
Author summary Interferons (IFNs) and pro-inflammatory cytokines are key
regulators of gene expression and antibacterial defense during Legionella
pneumophila infection. Here we demonstrate that production of these mediators
was largely or partly dependent on the cyclic GMP-AMP synthase (cGAS)-STING
pathway in human and murine cells. Cells of individuals carrying the common
HAQ allele of TMEM173/STING were strongly impaired in their ability to respond
to L. pneumophila, bacterial DNA or cyclic dinucleotides (CDNs), whereas the
R232H allele was only attenuated in sensing of exogenous CDNs. Importantly,
cGAS and STING contributed to antibacterial defense in mice during L.
pneumophila lung infection, and the allele frequency of HAQ TMEM173/STING, but
not of R232H TMEM173/STING, was increased in two independent cohorts of human
Legionnaires’ disease patients as compared to healthy controls. Hence, sensing
of bacterial DNA by the cGAS/STING pathway contributes to antibacterial
defense against L. pneumophila infection, and the hypomorphic variant HAQ
TMEM173/STING is associated with increased susceptibility to Legionnaires’
disease in humans