title: 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(-/-) andCard9(-/-) mice recruited reduced numbers of T cells, B cells, and neutrophils to the Coccidioides-infected hypodermis com pared to wild-type mice; however, neutrophils were dispensable for resistance to skin infection. Further studies have shown that gamma interferon (IFN-γ) 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-γ and nitric oxide production is essential for protection against subcutaneous Coccidioides infection.
authors: Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, Texas, USA Chiungyu.Hung@UTSA.edu.
authors: Chiung-Yu
authors: CY
authors: Hung
authors: Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, Texas, USA.
authors: Natalia
authors: N
authors: Castro-Lopez
authors: Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, Texas, USA.
authors: Garry T
authors: GT
authors: Cole
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D003045:Coccidioides / Q000502:physiology; D003047:Coccidioidomycosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D005786:Gene Expression Regulation / Q000502:physiology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology; D000096743:Interferon gamma Receptor
chemical_list: D053468:CARD Signaling Adaptor Proteins; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D053722:Receptors, Interleukin-17; D000096743:Interferon gamma Receptor; C513280:Card9 protein, mouse; C491673:Il17ra protein, mouse; C507780:Myd88 protein, mouse; C488842:Cybb protein, mouse