title: The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation.
abstract: Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Dana K
authors.initials: DK
authors.lastname: Shaw
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Holly L
authors.initials: HL
authors.lastname: Hammond
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Manira
authors.initials: M
authors.lastname: Rayamajhi
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Perkins
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Thangam S
authors.initials: TS
authors.lastname: Velayutham
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Evans
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Rodino
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.
authors.forename: Lauren
authors.initials: L
authors.lastname: VieBrock
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Scanlon
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Carbonetti
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Carlyon
authors.affiliation: Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Miao
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Jere W
authors.initials: JW
authors.lastname: McBride
authors.affiliation: Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Budweis, Czech Republic.
authors.forename: Michail
authors.initials: M
authors.lastname: Kotsyfakis
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Joao H F
authors.identifier: 0000-0001-8740-2667
authors.initials: JH
authors.lastname: Pedra
mesh_terms: D041081:Anaplasma phagocytophilum / Q000276:immunology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D002135:Calcium-Binding Proteins / Q000276:immunology*; D015232:Dinoprostone / Q000276:immunology*; D004195:Disease Models, Animal; D016873:Ehrlichiosis / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D058847:Inflammasomes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015232:Dinoprostone