ABSTRACT
Mucormycosis is an emerging fungal infection that is often lethal due to the ineffectiveness of current therapies. Here, we have studied the first stage of this infection-the germination of Mucor circinelloides spores inside phagocytic cells-from an integrated transcriptomic and functional perspective. A relevant fungal gene network is remodeled in response to phagocytosis, being enriched in crucial functions to survive and germinate inside the phagosome, such as nutritional adaptation and response to oxidative stress. Correspondingly, the phagocytic cells induced a specific proinflammatory and apoptotic response to the pathogenic strain. Deletion of fungal genes encoding putative transcription factors (atf1, atf2, and gcn4), extracellular proteins (chi1 and pps1), and an aquaporin (aqp1) revealed that these genes perform important roles in survival following phagocytosis, germination inside the phagosome, and virulence in mice. atf1 and atf2 play a major role in these pathogenic processes, since their mutants showed the strongest phenotypes and both genes control a complex gene network of secondarily regulated genes, including chi1 and aqp1 These new insights into the initial phase of mucormycosis define genetic regulators and molecular processes that could serve as pharmacological targets.IMPORTANCE Mucorales are a group of ancient saprophytic fungi that cause neglected infectious diseases collectively known as mucormycoses. The molecular processes underlying the establishment and progression of this disease are largely unknown. Our work presents a transcriptomic study to unveil the Mucor circinelloides genetic network triggered in fungal spores in response to phagocytosis by macrophages and the transcriptional response of the host cells. Functional characterization of differentially expressed fungal genes revealed three transcription factors and three extracellular proteins essential for the fungus to survive and germinate inside the phagosome and to cause disease in mice. Two of the transcription factors, highly similar to activating transcription factors (ATFs), coordinate a complex secondary gene response involved in pathogenesis. The significance of our research is in characterizing the initial stages that lead to evasion of the host innate immune response and, in consequence, the dissemination of the infection. This genetic study offers possible targets for novel antifungal drugs against these opportunistic human pathogens.
Subject(s)
Macrophages/microbiology , Mucor/growth & development , Mucormycosis/microbiology , Phagosomes/microbiology , Spores, Fungal/growth & development , Adaptation, Physiological , Animals , Cell Line , Disease Models, Animal , Gene Expression Profiling , Gene Expression Regulation, Fungal , Gene Regulatory Networks , Male , Mice , Mucormycosis/pathology , Survival Analysis , Virulence , Virulence Factors/genetics , Virulence Factors/metabolismABSTRACT
Mucormycosis is an emerging angio-invasive infection caused by Mucorales that presents unacceptable mortality rates. Iron uptake has been related to mucormycosis, since serum iron availability predisposes the host to suffer this infection. In addition, iron uptake has been described as a limiting factor that determines virulence in other fungal infections, becoming a promising field to study virulence in Mucorales. Here, we identified a gene family of three ferroxidases in Mucor circinelloides, fet3a, fet3b and fet3c, which are overexpressed during infection in a mouse model for mucormycosis, and their expression in vitro is regulated by the availability of iron in the culture media and the dimorphic state. Thus, only fet3a is specifically expressed during yeast growth under anaerobic conditions, whereas fet3b and fet3c are specifically expressed in mycelium during aerobic growth. A deep genetic analysis revealed partially redundant roles of the three genes, showing a predominant role of fet3c, which is required for virulence during in vivo infections, and shared functional roles with fet3b and fet3c during vegetative growth in media with low iron concentration. These results represent the first described functional specialization of an iron uptake system during fungal dimorphism.
Subject(s)
Ceruloplasmin/genetics , Fungal Proteins/genetics , Mucorales/enzymology , Mucorales/genetics , Mucormycosis/microbiology , Multigene Family , Virulence/genetics , Animals , Ceruloplasmin/metabolism , Fungal Proteins/metabolism , Gene Expression Regulation, Fungal , Genome, Fungal , Iron/metabolism , Male , Mice , Mucorales/growth & developmentABSTRACT
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Subject(s)
Female , Adult , Humans , Leiomyoma/surgery , Urogenital Surgical Procedures/methods , Anal Gland Neoplasms/surgery , Leiomyoma/diagnosis , Leiomyoma/pathology , Anal Gland Neoplasms/diagnosis , Anal Gland Neoplasms/pathologySubject(s)
Leiomyoma/diagnosis , Perineum , Soft Tissue Neoplasms/diagnosis , Female , Humans , Middle AgedABSTRACT
El carcinoma de mama es muy poco frecuente en el varón (0,1 a 0,2 por ciento de todos los cánceres masculinos), lo que condiciona diagnósticos más tardíos que ensombrecen el pronóstico. Se presentan una serie de 7 carcinomas de mama en 6 varones con edad media de 60 años (47 a 72 años) y tiempo medio primer síntoma-intervención de 14,3 meses (5 a 30 meses). Los estadios fueron I(1), II(3), III(1) y IV(1). El estudio histopatológico evidenció 6 carcinomas ductales infiltrantes (1 multicéntrico) y 1 intraductal (multicéntrico). Tratados 5 de ellos con mastectomía radical modificada, uno mediante mastectomía radical de Halsted y otro con tumorectomía simple + linfadenectomía axilar. Recibieron tratamiento coadyuvante 5 pacientes: 2 quimioterapia, 1 radioterapia, 1 quimioterapia + radioterapia y 1 hormonoterapia. Fallece uno al noveno día del posoperatorio por enfermedad diseminada en estadio terminal y otro a los 3,5 años de enfermedad metastásica; sobreviven los 4 restantes libres de enfermedad a los 7, 5, 5 y 5 años. Se analizan los aspectos diagnósticos y terapéuticos en una amplia revisión bibliográfica concluyendo que es una neoplasia de unas características y pronóstico similar en ambos sexos, si bien se publica peores resultados en el varón debido a la mayor demora en el diagnóstico respecto al femenino
