title: Innate immune recognition of flagellin limits systemic persistence of Brucella.
abstract: Brucella are facultative intracellular bacteria that cause chronic infections by limiting innate immune recognition. It is currently unknown whether Brucella FliC flagellin, the monomeric subunit of flagellar filament, is sensed by the host during infection. Here, we used two mutants of Brucella melitensis, either lacking or overexpressing flagellin, to show that FliC hinders bacterial replication in vivo. The use of cells and mice genetically deficient for different components of inflammasomes suggested that FliC was a target of the cytosolic innate immune receptor NLRC4 in vivo but not in macrophages in vitro where the response to FliC was nevertheless dependent on the cytosolic adaptor ASC, therefore suggesting a new pathway of cytosolic flagellin sensing. However, our work also suggested that the lack of TLR5 activity of Brucella flagellin and the regulation of its synthesis and/or delivery into host cells are both part of the stealthy strategy of Brucella towards the innate immune system. Nevertheless, as a flagellin-deficient mutant of B. melitensis wasfound to cause histologically demonstrable injuries in the spleen of infected mice, we suggested that recognition of FliC plays a role in the immunological stand-off between Brucella and its host, which is characterized by a persistent infection with limited inflammatory pathology.
authors.affiliation: URBM, University of Namur (FUNDP), Belgium.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Terwagne
authors.affiliation: URBM, University of Namur (FUNDP), Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ferooz
authors.affiliation: Department of Medical Microbiology & Immunology, University of California, Davis, CA, USA.
authors.forename: Hortensia G
authors.initials: HG
authors.lastname: Rolán
authors.affiliation: Department of Medical Microbiology & Immunology, University of California, Davis, CA, USA.
authors.forename: Yao-Hui
authors.initials: YH
authors.lastname: Sun
authors.affiliation: Department of Medical Microbiology & Immunology, University of California, Davis, CA, USA.
authors.forename: Vidya
authors.initials: V
authors.lastname: Atluri
authors.affiliation: Department of Medical Microbiology & Immunology, University of California, Davis, CA, USA.
authors.forename: Mariana N
authors.initials: MN
authors.lastname: Xavier
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
authors.affiliation: URBM, University of Namur (FUNDP), Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Legrand
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: URBM, University of Namur (FUNDP), Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: De Bolle
authors.affiliation: URBM, University of Namur (FUNDP), Belgium.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Letesson
authors.affiliation: Department of Medical Microbiology & Immunology, University of California, Davis, CA, USA.
authors.forename: Renée M
authors.initials: RM
authors.lastname: Tsolis
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D017347:Brucella melitensis / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D002006:Brucellosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D003106:Colon / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005408:Flagellin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D066298:In Vitro Techniques; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D051198:Toll-Like Receptor 5 / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C512299:Ipaf protein, mouse; D051198:Toll-Like Receptor 5; D005408:Flagellin