BAD1, an Essential Virulence Factor of<i>Blastomyces dermatitidis</i>, Suppresses Host TNF-α Production Through TGF-β-Dependent and -Independent Mechanisms

Finkel-Jimenez, Beatriz; Wüthrich, Marcel; Klein, Bruce S.

doi:10.4049/jimmunol.168.11.5746

Cited by 75 publications

(51 citation statements)

References 35 publications

(28 reference statements)

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“…Research done in Cryptococcus neoformans and Blastomyces dermatitis has demonstrated that fungal pathogens can modulate host cytokines via secreted or cell surface-localized proteins (8,27). Tumor necrosis factor alpha suppression by secreted and surface-localized Bad1 is the attribute of the protein that makes it a Blastomyces virulence factor (9).…”

Section: Discussionmentioning

confidence: 99%

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

Bohse

Woods

2005

Eukaryot Cell

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The YPS3 gene of Histoplasma capsulatum encodes a protein that is both resident in the cell wall and also released into the culture medium. This protein is produced only during the pathogenic yeast phase of infection and is also expressed differently in H. capsulatum strains that differ in virulence. We investigated the cellular localization of Yps3p. We demonstrated that the cell wall fraction of Yps3p was surface localized in restriction fragment length polymorphism class 2 strains. We also established that Yps3p released into the G217B culture supernatant binds to the surface of strains that do not naturally express the protein. This binding was saturable and occurred within 5 min of exposure and occurred similarly with live and heat-killed H. capsulatum. Flow cytometric analysis of H. capsulatum after enzymatic treatments was consistent with Yps3p binding to chitin, a carbohydrate polymer that is a component of fungal cell walls. Polysaccharide binding assays demonstrated that chitin but not cellulose binds to and extracts Yps3p from culture supernatants.

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Section: Discussionmentioning

confidence: 99%

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

Bohse

Woods

2005

Eukaryot Cell

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“…dermatitidis releases sBAD1 in quantity (up to 25 mg/l) during growth in vitro (18,29) and in the host lung alveolus during infection (7). In this study we analyzed the fate of sBAD1 after interaction with M, cells that mediate host defense against the fungus, but are also modulated by B. dermatitidis surface and sBAD1.…”

Section: Internalization Of Sbad1 By Mmentioning

confidence: 99%

“…We recently investigated BAD1 mechanisms that suppress TNF-␣ production (7). We found that BAD1 displayed on the surface of B. dermatitidis yeast induces phagocyte TGF-␤, which, in turn, suppresses TNF-␣ production.…”

mentioning

confidence: 99%

Exploiting Type 3 Complement Receptor for TNF-α Suppression, Immune Evasion, and Progressive Pulmonary Fungal Infection

Brandhorst

Wüthrich

Finkel-Jimenez

et al. 2004

The Journal of Immunology

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TNF-α is crucial in defense against intracellular microbes. Host immune cells use type 3 complement receptors (CR3) to regulate excess TNF-α production during physiological clearance of apoptotic cells. BAD1, a virulence factor of Blastomyces dermatitidis, is displayed on yeast and released during infection. BAD1 binds yeast to macrophages (Mφ) via CR3 and CD14 and suppresses TNF-α, which is required for resistance. We investigated whether blastomyces adhesin 1 (BAD1) exploits host receptors for immune deviation and pathogen survival. Soluble BAD1 rapidly entered Mφ, accumulated intracellularly by 10 min after introduction to cells, and trafficked to early and late endosomes. Inhibition of receptor recycling by monodansyl cadaverine blocked association of BAD1 with Mφ and reversed TNF-α suppression in vitro. Inhibition of BAD1 uptake with cytochalasin D and FcR-redirected delivery of soluble BAD1 as Ag-Ab complexes or of wild-type yeast opsonized with IgG similarly reversed TNF-α suppression. Hence, receptor-mediated entry of BAD1 is requisite in TNF-α suppression, and the route of entry is critical. Binding of soluble BAD1 to Mφ of CR3−/− and CD14−/− mice was reduced to 50 and 33%, respectively, of that in wild-type mice. Mφ of CR3−/− and CD14−/− mice resisted soluble BAD1 TNF-α suppression in vitro, but, in contrast to CR3−/− cells, CD14−/− cells were still subject to suppression mediated by surface BAD1 on wild-type yeast. CR3−/− mice resisted both infection and TNF-α suppression in vivo, in contrast to wild-type and CD14−/− mice. BAD1 of B. dermatitidis thus co-opts normal host cell physiology by exploiting CR3 to subdue TNF-α production and foster pathogen survival.

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“…Histoplasma yeast cells also produce Yps3 to promote extrapulmonary dissemination (Holbrook and Rappleye 2008). Similarly, the pathogenic Blastomyces yeast cells produce adhesin WI-1/Bad1 to suppress phagocyte proinflammatory responses, and Bad1 is indispensable for virulence of the fungus (Klein 2000;Rooney et al 2001;Finkel-Jimenez et al 2002).…”

Section: Morphotype Niche Adaptation and Fungal Virulencementioning

confidence: 99%

Fungal Morphogenesis

Lin

Alspaugh

Liu

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Morphogenesis in fungi is often induced by extracellular factors and executed by fungal genetic factors. Cell surface changes and alterations of the microenvironment often accompany morphogenetic changes in fungi. In this review, we will first discuss the general traits of yeast and hyphal morphotypes and how morphogenesis affects development and adaptation by fungi to their native niches, including host niches. Then we will focus on the molecular machinery responsible for the two most fundamental growth forms, yeast and hyphae. Last, we will describe how fungi incorporate exogenous environmental and host signals together with genetic factors to determine their morphotype and how morphogenesis, in turn, shapes the fungal microenvironment. PROPERTIES OF MORPHOGENESIS IN FUNGAL CELLS

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BAD1, an Essential Virulence Factor ofBlastomyces dermatitidis, Suppresses Host TNF-α Production Through TGF-β-Dependent and -Independent Mechanisms

Cited by 75 publications

References 35 publications

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

Exploiting Type 3 Complement Receptor for TNF-α Suppression, Immune Evasion, and Progressive Pulmonary Fungal Infection

Fungal Morphogenesis

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