Extracellular Superoxide Dismutase Protects Histoplasma Yeast Cells from Host-Derived Oxidative Stress

Abstract

In order to establish infections within the mammalian host, pathogens must protect themselves against toxic reactive oxygen species produced by phagocytes of the immune system. The fungal pathogen Histoplasma capsulatum infects both neutrophils and macrophages but the mechanisms enabling Histoplasma yeasts to survive in these phagocytes have not been fully elucidated. We show that Histoplasma yeasts produce a superoxide dismutase (Sod3) and direct it to the extracellular environment via N-terminal and C-terminal signals which promote its secretion and association with the yeast cell surface. This localization permits Sod3 to protect yeasts specifically from exogenous superoxide whereas amelioration of endogenous reactive oxygen depends on intracellular dismutases such as Sod1. While infection of resting macrophages by Histoplasma does not stimulate the phagocyte oxidative burst, interaction with polymorphonuclear leukocytes (PMNs) and cytokine-activated macrophages triggers production of reactive oxygen species (ROS). Histoplasma yeasts producing Sod3 survive co-incubation with these phagocytes but yeasts lacking Sod3 are rapidly eliminated through oxidative killing similar to the effect of phagocytes on Candida albicans yeasts. The protection provided by Sod3 against host-derived ROS extends in vivo. Without Sod3, Histoplasma yeasts are attenuated in their ability to establish respiratory infections and are rapidly cleared with the onset of adaptive immunity. The virulence of Sod3-deficient yeasts is restored in murine hosts unable to produce superoxide due to loss of the NADPH-oxidase function. These results demonstrate that phagocyte-produced ROS contributes to the immune response to Histoplasma and that Sod3 facilitates Histoplasma pathogenesis by detoxifying host-derived reactive oxygen thereby enabling Histoplasma survival.

Biochemical and Molecular Analysis of Superoxide Dismutase in Sordaria fimicola and Aspergillus niger Collected from Different Environments

“…Superoxide dismutase (SOD, EC 1.15.1.1) is present in all living organisms that efficiently transform superoxide (O 2 -) into hydrogen peroxide (H 2 O 2 ) and molecular oxygen [4]. Superoxide dismutases are well described in prokaryotic and eukaryotic cells and have proven to be universal protective tools that protect the cell from damage [5].…”

The superoxide dismutases of Candida glabrata protect against oxidative damage and are required for lysine biosynthesis, DNA integrity and chronological life survival

“…These findings support a model in which oxidative damage to biomolecules in the SOD mutants is superoxide-driven and is due mainly to iron release from the 4Fe-4S clusters. Moreover, SODs participate in the OSR and are associated with virulence in fungal pathogens like C. albicans or H. capsulatum (Hwang et al, 2002;Youseff et al, 2012). In this paper, we expand our knowledge about the roles of the superoxide dismutases in C. glabrata.…”

“…8). This is surprising since previous observations have proposed SODs as virulence factors in bacteria and pathogenic yeasts (Hwang et al, 2002;Langford et al, 2002;Narasipura et al, 2003;Youseff et al, 2012). This evidence indicates that there are additional factors that compensate for the lack of SODs in vivo.…”

“…gattii (Hwang et al, 2002;Narasipura et al, 2003;Youseff et al, 2012); however, the role of the SODs in C. glabrata has been only partially analysed (Cuéllar-Cruz et al, 2009;Roetzer et al, 2011). C. glabrata can withstand twice the concentration of menadione [MD, an oxidant that generates O 2 $2 through redox cycling (Hampsey, 1997)] compared with Sac.…”

A transcription factor, MrMsn2, in the dimorphic fungus Metarhizium rileyi is essential for dimorphism transition, aggravated pigmentation, conidiation and microsclerotia formation

“…Fungi have evolved effective antioxidant mechanisms that include enzyme families that act as ROS scavengers. Previous studies have shown members of antioxidant enzymes families such as SODs and CATs may have complementary effects during the cellular developmental processes (Xie et al ., 2012; Youseff et al ., 2012; Wang et al ., 2013; Zhang and Feng, 2018). Our investigations confirmed that antioxidant enzyme genes cat1 , sod1 , cat2 and sod2 had different expressions during conidia development in M. rileyi (Fig.…”