Card9- and MyD88-Mediated Gamma Interferon and Nitric Oxide Production Is Essential for Resistance to Subcutaneous Coccidioides posadasii Infection

Abstract

Coccidioidomycosis is a potentially life-threatening respiratory disease which is endemic to the southwestern United States and arid regions of Central and South America. It is responsible for approximately 150,000 infections annually in the United States alone. Almost every human organ has been reported to harbor parasitic cells of Coccidioides spp. in collective cases of the disseminated form of this mycosis. Current understanding of the mechanisms of protective immunity against lung infection has been largely derived from murine models of pulmonary coccidioidomycosis. However, little is known about the nature of the host response to Coccidioides in extrapulmonary tissue. Primary subcutaneous coccidioidal infection is rare but has been reported to result in disseminated disease. Here, we show that activation of MyD88 and Card9 signal pathways are required for resistance to Coccidioides infection following subcutaneous challenge of C57BL/6 mice, which correlates with earlier findings of the protective response to pulmonary infection. MyD88 ؊/؊ and Card9 ؊/؊ mice recruited reduced numbers of T cells, B cells, and neutrophils to the Coccidioides-infected hypodermis compared to wild-type mice; however, neutrophils were dispensable for resistance to skin infection. Further studies have shown that gamma interferon (IFN-␥) production and activation of Th1 cells characterize resistance to subcutaneous infection. Furthermore, activation of a phagosomal enzyme, inducible nitric oxide synthase, which is necessary for NO production, is a requisite for fungal clearance in the hypodermis. Collectively, our data demonstrate that MyD88-and Card9-mediated IFN-␥ and nitric oxide production is essential for protection against subcutaneous Coccidioides infection.T wo species of Coccidioides, C. immitis and C. posadasii, are soilborne molds and the etiologic agents of coccidioidomycosis, a potentially life-threatening human respiratory disease that is also known as San Joaquin Valley fever. This pulmonary mycosis is endemic to the southwestern United States and certain arid regions of Mexico, as well as Central and South America (1). Recent evidence has revealed that C. posadasii occurs in Washington State, well north of the previously documented boundary of regions of endemicity for coccidioidal infections in the United States (2). Coccidioides is a diphasic pathogen, characterized by a saprobic phase that produces dry, air-dispersed, infectious spores from vegetative mycelia and a parasitic cycle which is unique among the medically important fungi (3). Inhaled spores grow isotropically in the lungs of the mammalian host to form the first generation of parasitic cells (spherule initials). The spherule initials continue to enlarge and differentiate into multinucleate spherules (Ͼ80 m in diameter). The cytoplasm of these coenocytes undergoes a process of segmentation by invagination of the inner spherule wall layer, followed by the formation of a multitude of endospores, each 2 to 10 m in diameter. Endospores also undergo isotropic...

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