title: MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP.
abstract: Cyclic-di-GMP and cyclic-di-AMP are second messengers produced by bacteria and influence bacterial cell survival, differentiation, colonization, biofilm formation, virulence, and bacteria-host interactions. In this study, we show that in both RAW264.7 macrophage cells and primary bone marrow-derived macrophages, the production of IFN-β and IL-6, but not TNF, in response to cyclic-di-AMP and cyclic-di-GMP requires MPYS (also known as STING, MITA, and TMEM173). Furthermore, expression of MPYS was required for IFN response factor 3 but not NF-κB activation in response to these bacterial metabolites. We also confirm that MPYS is required for type I IFN production by cultured macrophages infected with the intracellular pathogens Listeria monocytogenes and Francisella tularensis. However, during systemic infection with either pathogen, MPYS deficiency did not impact bacterial burdens in infected spleens. Serum IFN-β and IL-6 concentrations in the infected control and MPYS(-/-) mice were also similar at 24 h postinfection, suggesting that these pathogens stimulate MPYS-independent cytokine production during in vivo infection. Our findings indicate that bifurcating MPYS-dependent and -independent pathways mediate sensing of cytosolic bacterial infections.
authors.affiliation: Integrated Department of Immunology, University of Colorado Denver School of Medicine, Denver, CO 80206, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Krista K
authors.initials: KK
authors.lastname: Hill
authors.forename: Holly
authors.initials: H
authors.lastname: Filak
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mogan
authors.forename: Heather
authors.initials: H
authors.lastname: Knowles
authors.forename: Bicheng
authors.initials: B
authors.lastname: Zhang
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Perraud
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
authors.forename: Laurel L
authors.initials: LL
authors.lastname: Lenz
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000276:immunology* / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D050838:Interferon Regulatory Factor-3 / Q000276:immunology* / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010586:Phagocytes; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099197:STING Protein
chemical_list: D000242:Cyclic AMP; D006152:Cyclic GMP; D016207:Cytokines; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C062025:bis(3',5')-cyclic diguanylic acid