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

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 unknow...

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Bibliographic Details
Published in:PLoS pathogens Vol. 14; no. 1; p. e1006829
Main Authors: Ruiz-Moreno, Juan S., Hamann, Lutz, Shah, Javeed A., Verbon, Annelies, Mockenhaupt, Frank P., Puzianowska-Kuznicka, Monika, Naujoks, Jan, Sander, Leif E., Witzenrath, Martin, Cambier, John C., Suttorp, Norbert, Schumann, Ralf R., Jin, Lei, Hawn, Thomas R., Opitz, Bastian
Format: Journal Article
Language:English
Published: United States Public Library of Science 01.01.2018
Public Library of Science (PLoS)
Subjects:
Adult
Aged
Aged, 80 and over
AMP
Analysis
Animal diseases
Animals
Anti-Bacterial Agents - therapeutic use
Antibacterial agents
Antiinfectives and antibacterials
Bacteria
Biology and Life Sciences
Case-Control Studies
Cells, Cultured
Clinical trials
Cyclic GMP
Cytokines
Deoxyribonucleic acid
Disease control
Disease susceptibility
DNA
Female
Gene expression
Genetic Predisposition to Disease
Haplotypes
Health aspects
HEK293 Cells
Humans
Immune response
Immunity, Innate - drug effects
Immunity, Innate - genetics
Infection
Infections
Infectious diseases
Inflammation
Internal medicine
Kinases
Legionella
Legionella pneumophila - immunology
Legionnaire's disease
Legionnaires' disease
Legionnaires' Disease - drug therapy
Legionnaires' Disease - genetics
Legionnaires' disease bacterium
Macrophages
Male
Medical research
Medicine
Medicine and Health Sciences
Membrane Proteins - genetics
Mice
Mice, Inbred C57BL
Middle Aged
Nucleotidyltransferases - physiology
Polymorphism, Genetic
Research and Analysis Methods
Treatment Outcome
Tuberculosis
Poland
United States > US
Germany
ISSN:1553-7374, 1553-7366, 1553-7374
Online Access:Get full text
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Summary: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. ClinicalTrials.gov DRKS00005274, German Clinical Trials Register.
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The authors have declared that no competing interests exist.
Membership of the CAPNETZ Study Group is provided in the Acknowledgments.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1006829