Interleukin-1 Receptor but Not Toll-Like Receptor 2 Is Essential for MyD88-Dependent Th17 Immunity to Coccidioides Infection

Hung, Chiung Yu; Jiménez-Alzate, María del Pilar; González, Ángel; Wüthrich, Marcel; Klein, Bruce S.; Cole, Garry T.

doi:10.1128/iai.01579-13

Cited by 32 publications

(45 citation statements)

References 52 publications

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“…Many studies of pulmonary coccidioidomycosis have reported IFN-␥ production as a correlate of vaccine-induced protection in mice (54,55). Surprisingly, we have found that the murine IL-17A and Th17 cells are essential for conferring resistance to pulmonary Coccidioides infection, while the IFN-␥ receptor and Th1 cells are dispensable (15,17,19). These results raise the possibility that there is a differential requirement of IFN-␥-and IL-17A-mediated immunity in defense against pulmonary and cutaneous coccidioidomycosis.…”

Section: Discussionmentioning

confidence: 69%

“…MyD88 and Card9 are two cytosolic immune adaptors that transduce signals from IL-1 receptor/Toll-like receptors (TIR/TLRs) and C-type lectin receptors (CLRs), respectively, to bridge innate and adaptive immunity (20,(40)(41)(42)(43)(44)(45). We recently reported that MyD88-and Card9-mediated signaling pathways contribute to the development of vaccine-induced Th17 and Th1 immunity against pulmonary Coccidioides infection (18,19). MyD88 signaling leads to the activation of protein kinases and the expression of transcription factors that trigger the expression of cytokines and inflammatory factors required for T cell development and differentiation (46).…”

Section: Discussionmentioning

confidence: 99%

“…Vaccine-induced activation of myeloid differentiation factor 88 (MyD88)-mediated and caspase adaptor recruitment domain family member 9 (Card9)-mediated immune responses have also been demonstrated to be necessary for resistance to pulmonary coccidioidomycosis (18,19). Both MyD88 and Card9 are required for differentiation and development of Th1 and Th17 immunity in Coccidioides-infected lungs (18,19). MyD88-and Card9-mediated signal pathways also facilitate microbe-induced production of reactive oxygen species (ROS) and nitric oxide (NO) (20)(21)(22)(23).…”

mentioning

confidence: 99%

“…The goals of this study were to establish a subcutaneously challenged murine model of coccidioidomycosis for determination of the nature of the host immune response to infection of the skin and to compare the results of histological and immunological examinations of subcutaneously challenged mice to those in reported studies of protective immunity in our pulmonary model of this respiratory disease (15)(16)(17)(18). The CD4 ϩ T cell-mediated response, especially Th1 and Th17 immunity, has been shown to be essential for resistance to pulmonary coccidioidal infection (15)(16)(17)(18)(19). Vaccine-induced activation of myeloid differentiation factor 88 (MyD88)-mediated and caspase adaptor recruitment domain family member 9 (Card9)-mediated immune responses have also been demonstrated to be necessary for resistance to pulmonary coccidioidomycosis (18,19).…”

mentioning

confidence: 99%

“…The CD4 ϩ T cell-mediated response, especially Th1 and Th17 immunity, has been shown to be essential for resistance to pulmonary coccidioidal infection (15)(16)(17)(18)(19). Vaccine-induced activation of myeloid differentiation factor 88 (MyD88)-mediated and caspase adaptor recruitment domain family member 9 (Card9)-mediated immune responses have also been demonstrated to be necessary for resistance to pulmonary coccidioidomycosis (18,19). Both MyD88 and Card9 are required for differentiation and development of Th1 and Th17 immunity in Coccidioides-infected lungs (18,19).…”

mentioning

confidence: 99%

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

2016

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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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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

2016

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Proper Care and Feeding of Coccidioides: A Laboratorian's Guide to Cultivating the Dimorphic Stages of C. immitis and C. posadasii

2020

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Coccidioides immitis and C. posadasii. These fungi are thermally dimorphic, cycling between mycelia and arthroconidia in the environment and converting into spherules and endospores within a host. Coccidioides can cause a broad spectrum of disease that can be difficult to treat. There has been a steady increase in disease, with an estimated 350,000 new infections per year in the United States. With the increase in disease and difficulty in treatment, there is an unmet need to increase research in basic biology and identify new treatments, diagnostics, and vaccine candidates. Here, we describe protocols required in any Coccidioides laboratory, such as growing, harvesting, and storing the different stages of this dimorphic fungal pathogen.

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Flow Cytometric Analysis of Protective T-Cell Response Against Pulmonary Coccidioides Infection

2016

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The incidence of systemic fungal infections has increased throughout the world, spurring much interest in developing effective vaccines. Coccidioidomycosis, also known as San Joaquin Valley fever, is a potentially life-threatening respiratory mycosis. A vaccine against Coccidioides infection would contribute significantly to the well-being of the approx. 30 million residents in the Southwestern USA as well as the multitude of travelers who annually visit the endemic regions. We have applied a live, attenuated vaccine (∆T) to explore the nature of vaccine immunity in mice after intranasal challenge with a potentially lethal dose of Coccidioides spores. Coccidioides spores are airborne and highly infectious for mammalian hosts and classified as a biosafety level 3 agent. T cells are critical in the development of protective immunity against a variety of microorganisms as well as the development of autoimmune disease and allergic responses. Profiles of cytokines detected in lung homogenates of ∆T-vaccinated mice were indicative of a mixed Th1, Th2, and Th17 immune response. We have developed an intracellular cytokine staining and flow cytometric (ICS) technique to measure activated CD4(+) and CD8(+) T cells and IFN-γ-, IL-4-, IL-5-, and IL-17A-producing T cells in the lungs of mice that are challenged with a potentially lethal dose of Coccidioides spores. The numbers of pulmonary Th1 and Th17 cells during the first 2 weeks post-challenge showed a progressive increase in vaccinated mice and corresponded with reduction of fungal burden. In this protocol, we describe the methodology for culture and isolation of the live, attenuated ΔT spores of Coccidioides used to vaccinate mice, preparation of pulmonary cells, and staining protocol for cell surface markers and intracellular cytokines. This is the most reliable and robust procedure to measure frequencies and numbers of each selected T-cell subsets in lungs of vaccinated versus control mice and can be readily applied to evaluate T-cell response against other microbial infections.

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Interleukin-1 Receptor but Not Toll-Like Receptor 2 Is Essential for MyD88-Dependent Th17 Immunity to Coccidioides Infection

Cited by 32 publications

References 52 publications

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

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

Proper Care and Feeding of Coccidioides: A Laboratorian's Guide to Cultivating the Dimorphic Stages of C. immitis and C. posadasii

Flow Cytometric Analysis of Protective T-Cell Response Against Pulmonary Coccidioides Infection

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