C-Type Lectin Receptors Differentially Induce Th17 Cells and Vaccine Immunity to the Endemic Mycosis of North America

Wang, Huafeng; LeBert, Vanessa; Hung, Chiung Yu; Galles, Kevin; Saijo, Shinobu; Lin, Xin; Cole, Garry T.; Klein, Bruce S.; Wüthrich, Marcel

doi:10.4049/jimmunol.1302314

Cited by 90 publications

(126 citation statements)

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“…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).…”

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confidence: 99%

“…Traumatic cutaneous inoculation of Coccidioides can result in prolonged illness and life-threatening disseminated disease, including coccidioidal meningitis (11)(12)(13)(14). 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).…”

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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).…”

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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).…”

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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: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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Fonsecaea pedrosoi‐induced Th17‐cell differentiation in mice is fostered by Dectin‐2 and suppressed by Mincle recognition

Wüthrich

Wang

et al. 2015

Eur J Immunol

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Chromoblastomycosis is a chronic skin infection caused by the pigmented saprophytic mould Fonsecaea pedrosoi. Chronicity of infection can be broken by a coordinated innate recognition of the spores by pattern recognition receptors. While Mincle signaling via theKeywords: Chromoblastomycosis r C-type lectin r Fungi r Dectin-2 r Mincle r T-cell differentiation r Th17 cell Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionChromoblastomycosis is a chronic progressive fungal infection of mammalian skin and subcutaneous tissue that is caused by which gradually enlarge and become verrucous nodules and psoriasis like plaques that may extend as satellites along the lymphatics or disseminate through scratching [5]. Chromoblastomycosis treatment is difficult and most therapeutic attempts provide only a modest rate of success [6,7].Little is known about the protective host defense mechanisms against chromoblastomycosis. Innate immunity mediated by neutrophils and macrophages is thought to be principally responsible for host protection [2,3]. However, the chronic nature of infection with F. pedrosoi may be due to an inappropriate innate immune response [8]. F. pedrosoi is recognized by the C-type lectin receptors (CLRs) Dectin-1 and Mincle, yet fails to induce the production of proinflammatory TNF-α by macrophages and DCs. Inflammatory responses to F. pedrosoi and clearance of infection can be reinstated by exogenous TLR costimulation [8]. Imiquimod (TLR7 ligand) and LPS (TLR4 ligand) application augments TNF-α production and accelerates healing in murine models [8] TLR costimulation does not augment Ag-specific T-cell development in F. pedrosoi-infected miceWe have previously shown that F. pedrosoi spores alone failed to induce innate inflammatory responses by macrophages. The failure of innate recognition could be reinstated by TLR costimulation [8]. To explore whether Ag-specific T-cell responses can be augmented by TLR costimulation we injected F. pedrosoi spore-infected mice with LPS as described [8]. Surprisingly, LPS (TLR4 agonist) and Imiquimod (TLR7 agonist) treatment did not increase the activation (CD44), expansion, and differentiation of Ag-specific 1807 cells as indicated by the numbers and frequencies of activated (CD44 + ) and cytokine producing (IFN-γ and IL-17) 1807 cells (Fig. 1A-E). Thus, unlike innate inflammatory responses, the generation of adaptive cell-mediated immune responses could not be augmented by costimulation of the TLR pathway. sought to investigate whether surface expressed CLRs are involved in the innate recognition of the fungal spores. We cocultured live F. pedrosoi spores with CLR transformed B3Z T-cell hybridoma cells expressing an NFAT-lacZ β-galatosidase reporter of ITAM signaling [15]. In response to spore stimulation, lacZ activity was increased in reporter cells expressing Dectin-1 and Dectin-2 and to a lesser extent MCL (Dectin-3, Clecsf8, or Clec4d) and Mincle, but not in cells expressing FcRγ only (Fig....

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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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C-Type Lectin Receptors Differentially Induce Th17 Cells and Vaccine Immunity to the Endemic Mycosis of North America

Cited by 90 publications

References 75 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

Fonsecaea pedrosoi‐induced Th17‐cell differentiation in mice is fostered by Dectin‐2 and suppressed by Mincle recognition

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

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