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TYPE I INTERFERON INDUCTION BY NEISSERIA GONORRHOEAE: DUAL REQUIREMENT OF CYCLIC GMP-AMP SYNTHASE AND TOLL-LIKE RECEPTOR 4
Author
Affilliation
University of Massachusetts Medical School. Division of Infectious Diseases. Worcester, MA, USA/University of Massachusetts Medical School. Department of Medicine. Program in Innate Immunity. Worcester, MA, USA
University of Massachusetts Medical School. Division of Infectious Diseases. Worcester, MA, USA
University of Massachusetts Medical School. Proteomics and Mass Spectrometry Facility. Worcester, MA, USA/University of Massachusetts Medical School. Department of Biochemistry and Molecular Pharmacology. Worcester, MA, USA
University of Massachusetts Medical School. Proteomics and Mass Spectrometry Facility. Worcester, MA, USA/University of Massachusetts Medical School. Department of Biochemistry and Molecular Pharmacology. Worcester, MA, USA
University of Wisconsin-Madison. Department of Medical Microbiology and Immunology. Madison, WI, USA
Universitätsklinikum Bonn. Institute of Molecular Medicine. Bonn,Germany
Universitätsklinikum Bonn. Institute of Molecular Medicine. Bonn,Germany Katherine A. Fitzgerald/University of Massachusetts Medical School. Division of Infectious Diseases. Worcester, MA, USA/University of Massachusetts Medical School. Department of Medicine. Program in Innate Immunity. Worcester, MA, USA/Norwegian University of Science and Technology. Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine. Trondheim, Norway
University of Massachusetts Medical School. Division of Infectious Diseases. Worcester, MA, USA/University of Massachusetts Medical School. Department of Medicine. Program in Innate Immunity.
University of Massachusetts Medical School. Division of Infectious Diseases. Worcester, MA, USA/ University of Massachusetts Medical School. Department of Medicine. Program in Innate Immunity/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brazil
University of Massachusetts Medical School. Division of Infectious Diseases. Worcester, MA, USA
University of Massachusetts Medical School. Proteomics and Mass Spectrometry Facility. Worcester, MA, USA/University of Massachusetts Medical School. Department of Biochemistry and Molecular Pharmacology. Worcester, MA, USA
University of Massachusetts Medical School. Proteomics and Mass Spectrometry Facility. Worcester, MA, USA/University of Massachusetts Medical School. Department of Biochemistry and Molecular Pharmacology. Worcester, MA, USA
University of Wisconsin-Madison. Department of Medical Microbiology and Immunology. Madison, WI, USA
Universitätsklinikum Bonn. Institute of Molecular Medicine. Bonn,Germany
Universitätsklinikum Bonn. Institute of Molecular Medicine. Bonn,Germany Katherine A. Fitzgerald/University of Massachusetts Medical School. Division of Infectious Diseases. Worcester, MA, USA/University of Massachusetts Medical School. Department of Medicine. Program in Innate Immunity. Worcester, MA, USA/Norwegian University of Science and Technology. Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine. Trondheim, Norway
University of Massachusetts Medical School. Division of Infectious Diseases. Worcester, MA, USA/University of Massachusetts Medical School. Department of Medicine. Program in Innate Immunity.
University of Massachusetts Medical School. Division of Infectious Diseases. Worcester, MA, USA/ University of Massachusetts Medical School. Department of Medicine. Program in Innate Immunity/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brazil
Abstract
The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC). Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN) production via TLR4/MD-2. In addition to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS), which produces 2′3′-cGAMP and triggers STING/TBK-1/IRF3 activation, resulting in type I IFN expression. Here, we reveal a cytosolic response to GC DNA that also contributes to type I IFN induction. We demonstrate that complete IFN-β induction by live GC depends on both cGAS and TLR4. Type I IFN is detrimental to the host, and dysregulation of iron homeostasis genes may explain lower bacteria survival in cGAS−/− and TLR4−/− cells. Collectively, these observations reveal cooperation between TLRs and cGAS in immunity to GC infection.
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