title: Modulation of the immune response by Fonsecaea pedrosoi morphotypes in the course of experimental chromoblastomycosis and their role on inflammatory response chronicity.
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.
authors.affiliation: Molecular Pathology Post-Graduate Program, School of Medicine; University of Brasília, Brasília, Brazil.
authors.forename: Isaque Medeiros
authors.initials: IM
authors.lastname: Siqueira
authors.affiliation: Molecular Pathology Post-Graduate Program, School of Medicine; University of Brasília, Brasília, Brazil.
authors.forename: Raffael Júnio Araújo
authors.initials: RJA
authors.lastname: de Castro
authors.affiliation: Department of Cell Biology, Institute of Biological Sciences; University of Brasília, Brasília, Brazil.
authors.forename: Luiza Chaves de Miranda
authors.initials: LCM
authors.lastname: Leonhardt
authors.affiliation: Department of Cell Biology, Institute of Biological Sciences; University of Brasília, Brasília, Brazil.
authors.forename: Márcio Sousa
authors.initials: MS
authors.lastname: Jerônimo
authors.affiliation: University Hospital, University of Brasília, Brasília, Brazil.
authors.forename: Aluízio Carlos
authors.initials: AC
authors.lastname: Soares
authors.affiliation: Institute Leônidas and Maria Deane, Oswaldo Cruz Foundation, Manaus, Brazil.
authors.forename: Tainá
authors.initials: T
authors.lastname: Raiol
authors.affiliation: School of Computing Sciences, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.
authors.forename: Christiane
authors.initials: C
authors.lastname: Nishibe
authors.affiliation: School of Computing Sciences, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.
authors.forename: Nalvo
authors.initials: N
authors.lastname: Almeida
authors.affiliation: Department of Cell Biology, Institute of Biological Sciences; University of Brasília, Brasília, Brazil.
authors.forename: Aldo Henrique
authors.initials: AH
authors.lastname: Tavares
authors.affiliation: Department of Cell Biology, Institute of Biological Sciences; University of Brasília, Brasília, Brazil.|Department of Food Sciences and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Christian
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Department of Cell Biology, Institute of Biological Sciences; University of Brasília, Brasília, Brazil.
authors.forename: Anamelia Lorenzetti
authors.initials: AL
authors.lastname: Bocca
mesh_terms: D000818:Animals; D017209:Apoptosis; D001203:Ascomycota / Q000502:physiology*; D002862:Chromoblastomycosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D059014:High-Throughput Nucleotide Sequencing; D054884:Host-Pathogen Interactions; D006801:Humans; D025301:Hyphae / Q000502:physiology; D037181:Lectins, C-Type / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010587:Phagocytosis / Q000276:immunology; D017423:Sequence Analysis, RNA; D013172:Spores, Fungal / Q000502:physiology; D015854:Up-Regulation; D000099181:Dectin-1
chemical_list: D016207:Cytokines; D037181:Lectins, C-Type; C546929:CLEC7A protein, human; D000099181:Dectin-1