Publikationsdatenbank

The hypomorphic HAQ variant of STING affects cGAS-dependent cytokine expression in response to bacterial infection and is associated with susceptibility to Legionnaires’ disease in humans (2019)

Art

Hochschulschrift

Autor

Ruiz-Moreno, Juan Sebastián (WE 6)

Quelle

Berlin: Mensch & Buch Verlag, 2019 — vi, 124 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/26577

Kontakt

Institut für Immunologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51834
immunologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Community-acquired pneumonia (CAP) remains one of the most notorious burdens for health worldwide. Among the wide spectrum of etiological agents, S. pneumoniae and L. pneumophila are considered two of the most common causes of bacterial CAP. Innate immune defenses against these and several other pathogens, largely relies on activation of pattern recognition receptors (PRRs) and initiation of inflammatory responses. Infection with L. pneumophila and S. pneumoniae has been previously shown to induce type I IFN responses in a manner dependent of STING. This protein is an essential adaptor of the cytosolic DNA sensor cGAS. Interestingly, two allelic variants of the STING-encoding gene TMEM173, namely HAQ and R232H, have been described before to have a diminished capacity of inducing type I IFN responses when ectopically expressed. The function of endogenous HAQ and R232H STING variants and their potential association with predisposition to infectious diseases have, however, not yet been assessed. Here, I show that the cGAS-STING pathway mediates detection of S. pneumoniae and L. pneumophila infection to primarily stimulate type I IFN responses. Cells of human individuals carrying HAQ TMEM173 were largely or partly defective in inducing type I IFNs and proinflammatory cytokines upon bacterial infection or stimulation with bacterial DNA and cyclic di-nucleotides (CDNs). In contrast, cells expressing R232H STING were partly impaired in their response to CDNs but responded normally to L. pneumophila and S. pneumoniae. Subsequent analyses revealed that the STING pathway contributed to control of L. pneumophila infection but was dispensable for restricting S. pneumoniae during acute pneumonia in mice. Moreover, explorative analyses revealed an association of HAQ TMEM173 with susceptibility to L. pneumophila but not with S. pneumoniae infection in humans. Our study reveals that the cGAS-STING cascade contributes to antibacterial defense against L. pneumophila but not S. pneumoniae in mice and humans, and provides important insight into how the common HAQ TMEM173/STING variant affects antimicrobial immune responses and susceptibility to infection.