The WI-1 Adhesin Blocks Phagocyte TNF-α Production, Imparting Pathogenicity on Blastomyces dermatitidis

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-α 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-α production, yet WI-1 knockout yeast stimulated production. Coating knockout yeast with purified WI-1 converted them from stimulating TNF-α production to inhibiting production. Addition of purified WI-1 into stimulated phagocyte cultures led to concentration-dependent inhibition of TNF-α production. Neutralization of TNF-α in vivo exacerbated experimental pulmonary infection, particularly for the nonpathogenic WI-1 knockout yeast. Inducing increased TNF-α 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-α production by phagocytes, which fosters progression of pulmonary infection.

Transient Neutralization of Tumor Necrosis Factor Alpha Can Produce a Chronic Fungal Infection in an Immunocompetent Host: Potential Role of Immature Dendritic Cells

“…In agreement with these observations, a number of highly virulent isolates of C. neoformans do not induce early TNF-␣ production following infection (22,34). Inhibition of TNF-␣ production by the virulence factor W-1 of B. dermatitidis has also been reported (13). Thus, fungi produce a number of virulence factors capable of down-regulating TNF-␣ production by the host, thereby promoting chronic infection.…”

Induction of Interleukin-12 and Gamma Interferon Requires Tumor Necrosis Factor Alpha for Protective T1-Cell-Mediated Immunity to PulmonaryCryptococcus neoformansInfection

“…In addition, cryptococcal polysaccharide capsule can induce IL-10 (a potent antagonist of TNF-␣ production) and induce TNF receptor shedding (8,22,38). The virulence factor W-1 of Blastomyces dermatitidis can also inhibit TNF-␣ production (9). Consistent with these observations is that highly virulent isolates of C. neoformans induce significantly less TNF-␣ following infection (13,18,29).…”

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

“…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).…”