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Nat Immunol. 2015 May;16(5):476-484. doi: 10.1038/ni.3119. Epub 2015 Mar 16.

Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida.

Author information

1
Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
2
CIRI, Inserm U1111, CNRS UMR 5308, Université Claude Bernard Lyon-1, Ecole Normale Supérieure, Lyon, France.
3
SFR Biosciences, UMS344/US8, Inserm, CNRS, Université Claude Bernard Lyon-1, Ecole Normale Supérieure, Lyon, France.
4
Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany.
5
Department of Microbiology and Immunology, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan.
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Contributed equally

Abstract

The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines interleukin 1β (IL-1β) and IL-18. AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as Francisella tularensis subspecies novicida (F. novicida). The activation of AIM2 by F. novicida requires bacteriolysis, yet whether this process is accidental or is a host-driven immunological mechanism has remained unclear. By screening nearly 500 interferon-stimulated genes (ISGs) through the use of small interfering RNA (siRNA), we identified guanylate-binding proteins GBP2 and GBP5 as key activators of AIM2 during infection with F. novicida. We confirmed their prominent role in vitro and in a mouse model of tularemia. Mechanistically, these two GBPs targeted cytosolic F. novicida and promoted bacteriolysis. Thus, in addition to their role in host defense against vacuolar pathogens, GBPs also facilitate the presentation of ligands by directly attacking cytosolic bacteria.

PMID:
25774716
PMCID:
PMC4568307
DOI:
10.1038/ni.3119
[Indexed for MEDLINE]
Free PMC Article

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