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.

Histoplasma capsulatum Depends on De Novo Vitamin Biosynthesis for Intraphagosomal Proliferation

“…Infection of macrophages by yeast cells is facilitated by binding of yeasts to complement receptors and internalization into phagosomes (3,4). Survival of the initial encounter with microbicidal phagocytes is enhanced by elimination of phagocyte-produced reactive oxygen through yeast-expressed extracellular superoxide dismutase and catalase (5,6).…”

Glycosylation and Immunoreactivity of the Histoplasma capsulatum Cfp4 Yeast-Phase Exoantigen

“…In contrast, Cfp4 is one of the most abundantly secreted proteins by wild-type strains. Alternatively, Cfp4's role in pathogenesis may be masked by another factor with redundant function, as was observed with CatB and an intracellular catalase, CatP (10). As a third possibility, Cfp4's pathogenesis function may be specific for human but not murine hosts.…”

“…Virulence is a unique feature of the yeast phase of Histoplasma, and nearly all demonstrated virulence factors exhibit preferential production by yeast cells instead of mycelia (Cbp1, ␣-1,3-glucan, Sod3, CatB, and Yps3) (9,10,19,24,37,38). The Cfp4 protein shares many characteristics with established Histoplasma virulence factors, including yeast-phase-specific production, extracellular localization, and conserved production among three separate phylogenetic groups.…”

“…By expression of an ␣-linked glucan cell wall polysaccharide, Histoplasma yeasts conceal immunostimulatory cell wall ␤-glucans from detection by phagocytes (8). In addition, Histoplasma yeasts express an extracellular oxidative stress response system consisting of the extracellular superoxide dismutase, Sod3, and the extracellular catalase, CatB (9,10). These secreted and cell surface-localized factors protect Histoplasma yeasts from the antimicrobial phagocyte-produced reactive oxygen during uptake by host phagocytes.…”

Six Key Traits of Fungi: Their Evolutionary Origins and Genetic Bases

“…Such strategies include masking their pathogenassociated danger signals, altering fungal signaling pathways, and promoting intracellular survival. An additional example is the oxidative stress-evading strategy of H. capsulatum and P. brasiliensis (28)(29)(30). Both species evolved their own nitric oxide reductase and several catalase enzymes to overcome the effect of reactive oxygen and nitrogen species produced by host cells.…”