期刊
JOURNAL OF IMMUNOLOGY
卷 166, 期 4, 页码 2665-2673出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.166.4.2665
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- NIAID NIH HHS [AI35681, AI40996] Funding Source: Medline
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-l knockout yeast stimulated production. Coating knockout yeast with purified WI-1 converted them from stimulating TNF-gamma production to inhibiting production. Addition of purified WI-I 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-a production by phagocytes, which fosters progression of pulmonary infection.
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