title: Rickettsia australis Activates Inflammasome in Human and Murine Macrophages.
abstract: Rickettsiae actively escape from vacuoles and replicate free in the cytoplasm of host cells, where inflammasomes survey the invading pathogens. In the present study, we investigated the interactions of Rickettsia australis with the inflammasome in both mouse and human macrophages. R. australis induced a significant level of IL-1β secretion by human macrophages, which was significantly reduced upon treatment with an inhibitor of caspase-1 compared to untreated controls, suggesting caspase-1-dependent inflammasome activation. Rickettsia induced significant secretion of IL-1β and IL-18 in vitro by infected mouse bone marrow-derived macrophages (BMMs) as early as 8-12 h post infection (p.i.) in a dose-dependent manner. Secretion of these cytokines was accompanied by cleavage of caspase-1 and was completely abrogated in BMMs deficient in caspase-1/caspase-11 or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), suggesting that R. australis activate the ASC-dependent inflammasome. Interestingly, in response to the same quantity of rickettsiae, NLRP3-/- BMMs significantly reduced the secretion level of IL-1β compared to wild type (WT) controls, suggesting that NLRP3 inflammasome contributes to cytosolic recognition of R. australis in vitro. Rickettsial load in spleen, but not liver and lung, of R. australis-infected NLRP3-/- mice was significantly greater compared to WT mice. These data suggest that NLRP3 inflammasome plays a role in host control of bacteria in vivo in a tissue-specific manner. Taken together, our data, for the first time, illustrate the activation of ASC-dependent inflammasome by R. australis in macrophages in which NLRP3 is involved.
authors.affiliation: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Smalley
authors.affiliation: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bechelli
authors.affiliation: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Dedeke
authors.initials: D
authors.lastname: Rockx-Brouwer
authors.affiliation: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Tais
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Sasha R
authors.initials: SR
authors.lastname: Azar
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Nahed
authors.initials: N
authors.lastname: Ismail
authors.affiliation: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: David H
authors.initials: DH
authors.lastname: Walker
authors.affiliation: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Fang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000382:microbiology; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D012281:Rickettsia / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism / Q000382:microbiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C498534:Pycard protein, mouse; D020170:Caspase 1