title: NLRC4 and TLR5 each contribute to host defense in respiratory melioidosis.
abstract: Burkholderia pseudomallei causes the tropical infection melioidosis. Pneumonia is a common manifestation of melioidosis and is associated with high mortality. Understanding the key elements of host defense is essential to developing new therapeutics for melioidosis. As a flagellated bacterium encoding type III secretion systems, B. pseudomallei may trigger numerous host pathogen recognition receptors. TLR5 is a flagellin sensor located on the plasma membrane. NLRC4, along with NAIP proteins, assembles a canonical caspase-1-dependent inflammasome in the cytoplasm that responds to flagellin (in mice) and type III secretion system components (in mice and humans). In a murine model of respiratory melioidosis, Tlr5 and Nlrc4 each contributed to survival. Mice deficient in both Tlr5 and Nlrc4 were not more susceptible than single knockout animals. Deficiency of Casp1/Casp11 resulted in impaired bacterial control in the lung and spleen; in the lung much of this effect was attributable to Nlrc4, despite relative preservation of pulmonary IL-1β production in Nlrc4(-/-) mice. Histologically, deficiency of Casp1/Casp11 imparted more severe pulmonary inflammation than deficiency of Nlrc4. The human NLRC4 region polymorphism rs6757121 was associated with survival in melioidosis patients with pulmonary involvement. Co-inheritance of rs6757121 and a functional TLR5 polymorphism had an additive effect on survival. Our results show that NLRC4 and TLR5, key components of two flagellin sensing pathways, each contribute to host defense in respiratory melioidosis.
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America; International Respiratory and Severe Illness Center, University of Washington, Seattle, Washington, United States of America; Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: T Eoin
authors.initials: TE
authors.lastname: West
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Nicolle D
authors.initials: ND
authors.lastname: Myers
authors.affiliation: Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Narisara
authors.initials: N
authors.lastname: Chantratita
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Wirongrong
authors.initials: W
authors.lastname: Chierakul
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Direk
authors.initials: D
authors.lastname: Limmathurotsakul
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Vanaporn
authors.initials: V
authors.lastname: Wuthiekanun
authors.affiliation: Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, and Center for Gastrointestinal Biology and Disease, 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 Comparative Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Adeline M
authors.initials: AM
authors.lastname: Hajjar
authors.affiliation: Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Peacock
authors.affiliation: Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: H Denny
authors.initials: HD
authors.lastname: Liggitt
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Skerrett
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D016957:Burkholderia pseudomallei / Q000276:immunology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D005408:Flagellin / Q000276:immunology; D006801:Humans; D008554:Melioidosis / Q000276:immunology*; D051379:Mice; D012141:Respiratory Tract Infections / Q000276:immunology / Q000382:microbiology*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C512299:Ipaf protein, mouse; D051198:Toll-Like Receptor 5; D005408:Flagellin