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The WI-1 adhesin blocks phagocyte TNF-alpha production, imparting pathogenicity on Blastomyces dermatitidis
B Finkel-Jimenez1, M Wüthrich, T Brandhorst
1Department of Pediatrics, Comprehensive Cancer Center, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI, USA.
Abstract:
The WI-1 adhesin is indispensable for pathogenicity of Blastomyces dermatitidis and is thought to promote pulmonary infection by fixing yeast to lung tissue and cells. Recent findings suggest that WI-1 confers pathogenicity by mechanisms in addition to adherence. Here, we investigated whether WI-1 modulates host immunity by altering production of pro-inflammatory cytokines. Production of TNF-alpha in lung alveolar fluids of mice infected with B. dermatitidis was severalfold higher for WI-1 knockout yeast compared with wild-type yeast, and in vitro coculture of unseparated lung cells with these isogenic yeast disclosed similar differences. Upon coculture with purified macrophages and neutrophils, wild-type yeast blocked TNF-alpha production, yet WI-1 knockout yeast stimulated production. Coating knockout yeast with purified WI-1 converted them from stimulating TNF-alpha production to inhibiting production. Addition of purified WI-1 into stimulated phagocyte cultures led to concentration-dependent inhibition of TNF-alpha production. Neutralization of TNF-alpha in vivo exacerbated experimental pulmonary infection, particularly for the nonpathogenic WI-1 knockout yeast. Inducing increased TNF-alpha levels in the lung by adenovirus-vectored gene therapy controlled infection with wild-type yeast. Thus, the WI-1 adhesin on yeast modulates host immunity through blocking TNF-alpha production by phagocytes, which fosters progression of pulmonary infection.
Insights
The WI-1 adhesin on Blastomyces dermatitidis inhibits TNF-alpha production by immune cells, promoting lung infections. Boosting TNF-alpha levels controlled fungal infections in mice.
Area of Science:
- Mycology
- Immunology
- Pathogenesis
Background:
- The WI-1 adhesin is crucial for Blastomyces dermatitidis pathogenicity, primarily by facilitating yeast adherence to lung tissues.
- Emerging evidence suggests WI-1's role extends beyond adherence, potentially influencing host immune responses.
Purpose of the Study:
- To investigate if WI-1 modulates host immunity by altering pro-inflammatory cytokine production, specifically TNF-alpha.
- To elucidate the mechanisms by which WI-1 contributes to pulmonary fungal infections.
Main Methods:
- Comparing TNF-alpha production in mouse lung fluids infected with wild-type and WI-1 knockout B. dermatitidis.
- In vitro coculture experiments with lung cells, macrophages, and neutrophils exposed to different yeast strains and purified WI-1.
- In vivo experiments involving TNF-alpha neutralization and gene therapy to modulate TNF-alpha levels.
Main Results:
- WI-1 knockout yeast elicited higher TNF-alpha production compared to wild-type yeast in vivo and in vitro.
- Wild-type yeast inhibited TNF-alpha production, while WI-1 knockout yeast stimulated it; purified WI-1 reversed this effect.
- In vivo TNF-alpha neutralization worsened infection, whereas increased lung TNF-alpha levels controlled wild-type yeast infections.
Conclusions:
- The WI-1 adhesin actively suppresses phagocyte TNF-alpha production, thereby facilitating the progression of Blastomyces dermatitidis pulmonary infections.
- Targeting TNF-alpha represents a potential therapeutic strategy for managing B. dermatitidis infections.