Abstract
A common theme across multiple fungal pathogens is their ability to impair the establishment of a protective immune response. Although early inflammation is beneficial in containing the infection, an uncontrolled inflammatory response is detrimental and may eventually oppose disease eradication. Chromoblastomycosis (CBM), a cutaneous and subcutaneous mycosis, caused by dematiaceous fungi, is capable of inducing a chronic inflammatory response. Muriform cells, the parasitic form of Fonsecaea pedrosoi, are highly prevalent in infected tissues, especially in long-standing lesions. In this study we show that hyphae and muriform cells are able to establish a murine CBM with skin lesions and histopathological aspects similar to that found in humans, with muriform cells being the most persistent fungal form, whereas mice infected with conidia do not reach the chronic phase of the disease. Moreover, in injured tissue the presence of hyphae and especially muriform cells, but not conidia, is correlated with intense production of pro-inflammatory cytokines in vivo. High-throughput RNA sequencing analysis (RNA-Seq) performed at early time points showed a strong up-regulation of genes related to fungal recognition, cell migration, inflammation, apoptosis and phagocytosis in macrophages exposed in vitro to muriform cells, but not conidia. We also demonstrate that only muriform cells required FcγR and Dectin-1 recognition to be internalized in vitro, and this is the main fungal form responsible for the intense inflammatory pattern observed in CBM, clarifying the chronic inflammatory reaction observed in most patients. Furthermore, our findings reveal two different fungal-host interaction strategies according to fungal morphotype, highlighting fungal dimorphism as an important key in understanding the bipolar nature of inflammatory response in fungal infections.
Highlights
A common theme observed across multiple fungal pathogens is their ability to impair the establishment of a protective immune response
Muriform cells were responsible for inflammatory response and conidia were related to fungus persistence in the tissue, highlighting fungal dimorphism as an important element in understanding the bipolar nature of the inflammatory response in some fungal infections
In this study we show that F. pedrosoi hyphae (FH) and muriform cells are able to establish a murine CBM displaying skin lesions and histopathological features similar to that found in humans, with muriform cells being the most persistent fungal morphotype, whereas mice infected with F. pedrosoi conidia do not reach the chronic phase of the disease
Summary
A common theme observed across multiple fungal pathogens is their ability to impair the establishment of a protective immune response. Disease chronicity may be the result of an exaggerated inflammatory response that probably compromises the host’s ability to cope with infective fungi, as opposed to an ‘intrinsic’ susceptibility to infection [2]. Chromoblastomycosis (CBM) is a cutaneous and subcutaneous mycosis, caused by dematiaceous fungi, which is capable of inducing a chronic inflammatory response, making it a suitable model to study chronic inflammation caused by dimorphic fungal infection. Despite occurring worldwide, it has a high prevalence in humid areas of tropical and subtropical climate [5,6]. CBM patients usually present low disease resolution and high relapse rates after treatment, which includes long-term antifungal chemotherapy and is often combined with physical and surgical treatment [9]
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