Transformation of Fonsecaea pedrosoi into sclerotic cells links to the refractoriness of experimental chromoblastomycosis in BALB/c mice via a mechanism involving a chitin-induced impairment of IFN-γ production

摘要

Chromoblastomycosis is a chronic, often debilitating, suppurative, granulomatous mycosis of the skin and subcutaneous tissues beginning after traumatic implantation of melanized fungi, of which Fonsecaea pedrosoi (F. pedrosoi) is considered the most common agent. Data suggest that the morphological transformation to the sclerotic cell form is linked to impaired clearance of the fungus in infected tissue. Notably, previous studies showed that the CD4+ T lymphocytes play an active role in host defense against F. pedrosoi in murine chromoblastomycosis and that a relatively low level of Th1 cytokine INF-γ and inefficient T cell proliferation are present in patients with the severe form of chromoblastomycosis. In the present work, by studying the BALB/c mice intraperitoneally infected with F. pedrosoi-spores, -hyphae or in vitro-induced sclerotic cells respectively, we demonstrate that the transformation of this agent into sclerotic cells contributes to a compromised Th1 cytokine production in the earlier stage of infection with impaired neutrophil ROS generation and pan-inhibition of Th1/Th2/Th17 cytokine production with disseminated infection in the later stage. In addition, we have further demonstrated that intraperitoneal administration of exogeneous IFN-γ greatly reduces the fungal load in the spleens of BALB/c mice infected with F. pedrosoi-sclerotic cells and inhibits the peritoneal dissemination of this agent. Meanwhile, exogeneous IFN-γ contributes to the formation and maintenance of micro-abscess and restores the decrease in neutrophil ROS generation in the nidus. Importantly, we have for the first time demonstrated that exclusive accumulation of chitin on the outer cell wall of F. pedrosoi-sclerotic cells, but not the -spores or -hyphae, contributes to an impaired murine Th1 cytokine production upon in vivo stimulation with this agent.