Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4

Warrison A Andrade; Sarika Agarwal; Shunyan Mo; Scott A Shaffer; Joseph P Dillard; Tobias Schmidt; Veit Hornung; Katherine A Fitzgerald; Evelyn A Kurt-Jones; Douglas T Golenbock

doi:10.1016/j.celrep.2016.05.030

Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4

Cell Rep. 2016 Jun 14;15(11):2438-48. doi: 10.1016/j.celrep.2016.05.030. Epub 2016 Jun 2.

Affiliations

¹ 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.
² Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01605, USA.
³ 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.
⁴ Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁵ Institute of Molecular Medicine, Universitätsklinikum Bonn, Bonn 53127, Germany.
⁶ 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.
⁷ 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.

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.

Keywords: Neisseria gonorrhoeae; STING; TLR4; cGAS; type I interferon.

MeSH terms

Bacterial Secretion Systems
Cell Line
DNA, Bacterial / metabolism
Humans
Interferon Type I / metabolism*
Iron / metabolism
Membrane Proteins / metabolism
Microbial Viability
Neisseria gonorrhoeae / physiology*
Nucleotides, Cyclic / metabolism
Nucleotidyltransferases / metabolism*
Toll-Like Receptor 4 / metabolism*
Transfection

Substances

Bacterial Secretion Systems
DNA, Bacterial
Interferon Type I
Membrane Proteins
Nucleotides, Cyclic
STING1 protein, human
Sting1 protein, mouse
Toll-Like Receptor 4
cyclic guanosine monophosphate-adenosine monophosphate
Iron
Nucleotidyltransferases
cGAS protein, human

Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4

Authors

Affiliations

Abstract

MeSH terms

Substances

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