title: Redundant catalases detoxify phagocyte reactive oxygen and facilitate Histoplasma capsulatum pathogenesis.
abstract: Histoplasma capsulatum is a respiratory pathogen that infects phagocytic cells. The mechanisms allowing Histoplasma to overcome toxic reactive oxygen molecules produced by the innate immune system are an integral part of Histoplasma's ability to survive during infection. To probe the contribution of Histoplasma catalases in oxidative stress defense, we created and analyzed the virulence defects of mutants lacking CatB and CatP, which are responsible for extracellular and intracellular catalase activities, respectively. Both CatB and CatP protected Histoplasma from peroxide challenge in vitro and from antimicrobial reactive oxygen produced by human neutrophils and activated macrophages. Optimal protection required both catalases, as the survival of a double mutant lacking both CatB and CatP was lower than that of single-catalase-deficient cells. Although CatB contributed to reactive oxygen species defenses in vitro, CatB was dispensable for lung infection and extrapulmonary dissemination in vivo. Loss of CatB from a strain also lacking superoxide dismutase (Sod3) did not further reduce the survival of Histoplasma yeasts. Nevertheless, some catalase function was required for pathogenesis since simultaneous loss of both CatB and CatP attenuated Histoplasma virulence in vivo. These results demonstrate that Histoplasma's dual catalases comprise a system that enables Histoplasma to efficiently overcome the reactive oxygen produced by the innate immune system.
authors.affiliation: Department of Microbiology, Ohio State University, Columbus, Ohio, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Holbrook
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Smolnycki
authors.forename: Brian H
authors.initials: BH
authors.lastname: Youseff
authors.forename: Chad A
authors.initials: CA
authors.lastname: Rappleye
mesh_terms: D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D006658:Histoplasma / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity*; D006660:Histoplasmosis / Q000382:microbiology / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism* / Q000382:microbiology; D018384:Oxidative Stress; D012331:RNA, Fungal / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D012331:RNA, Fungal; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase