Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4.
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.
Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Warrison A
WA
Andrade
Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Sarika
S
Agarwal
Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Shunyan
S
Mo
Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Scott A
SA
Shaffer
Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Joseph P
JP
Dillard
Institute of Molecular Medicine, Universitätsklinikum Bonn, Bonn 53127, Germany.
Tobias
T
Schmidt
Institute of Molecular Medicine, Universitätsklinikum Bonn, Bonn 53127, Germany.
Veit
V
Hornung
Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7489 Trondheim, Norway.
Katherine A
KA
Fitzgerald
Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Evelyn A
EA
Kurt-Jones
Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG 30190-002, Brazil. Electronic address: douglas.golenbock@umassmed.edu.
Douglas T
DT
Golenbock
D058947:Bacterial Secretion Systems; D002460:Cell Line; D004269:DNA, Bacterial / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D050296:Microbial Viability; D009344:Neisseria gonorrhoeae / Q000502:physiology*; D009712:Nucleotides, Cyclic / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014162:Transfection; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
D058947:Bacterial Secretion Systems; D004269:DNA, Bacterial; D007370:Interferon Type I; D007501:Iron; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D051197:Toll-Like Receptor 4; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
Neisseria gonorrhoeae; STING; TLR4; cGAS; type I interferon