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

Abstract

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....

Chromoblastomycosis

“…Several potential virulence factors are probably involved in this disease, including modifications of the cell surface, hydrophobicity, remodeling of the fungal cell wall, secretion of proteolytic and hydrolytic enzymes, adhesion molecules, incorporation of aromatic hydrocarbons, assembly of siderophores, and especially the presence of melanin. Most of the virulence and pathogenic factors observed in chromoblastomycotic infections are largely similar to those for infections by other pathogenic fungi (160)(161)(162)(163). Factors that are significant for the pathogenicity of CBM are melanin, muriform cells, cell adhesion, and hydrophobicity.…”

“…Recent studies have shown that impaired fungal clearance in CBM infections is due mainly to the enhanced virulence and pathogenicity of the etiological agents (159)(160)(161). Several potential virulence factors are probably involved in this disease, including modifications of the cell surface, hydrophobicity, remodeling of the fungal cell wall, secretion of proteolytic and hydrolytic enzymes, adhesion molecules, incorporation of aromatic hydrocarbons, assembly of siderophores, and especially the presence of melanin.…”

The C-Type Lectin Receptor MCL Mediates Vaccine-Induced Immunity against Infection with Blastomyces dermatitidis

“…MCL also has been shown to play a protective role in innate host defense against Gram-negative pneumonia (22). Aside from studies with C. albicans and Fonsecaea pedrosoi (13,23), the role of MCL in antifungal immunity remains poorly defined. Interestingly, MCL was shown to form a heterodimer with Dectin-2 to synergistically induce NF-B in response to C. albicans hyphae (24).…”

Antifungal Innate Immunity: A Perspective from the Last 10 Years

“…In vivo, dectin-2 has been shown to exert a protective role against C. albicans, C. glabrata , and T. rubrum infections [31] and, together with MCL, they have been suggested to promote Th17 responses to Fonsecaea pedrosoi and Blastomyces dermatitidis, respectively [32, 33], while Mincle can antagonize these responses [32]. Mice deficient in MCL show impaired vaccine resistance against B. dermatitidis infections, and this lack of resistance was associated with a reduced recruitment of Th17 cells to the lung upon recall following experimental challenge [33].…”