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.
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.
Prunus species are important crops in temperate regions. In these regions, drought periods are predicted to occur more frequently due to climate change. In this sense, to reduce the impact of climate warming, obtaining new tolerant/resistant cultivars and rootstocks is a mandatory goal in Prunus breeding. Therefore, the current study assembled three Prunus species including almond, (P. dulcis Mill D.A. Webb), apricot (P. armeniaca L.) and peach (P. persica L.) to model the temporal effects of drought. A hybrid peach × almond and a wild almond-relative species Prunus webbii were also included in the study. Physiological traits associated with photosynthetic activity, leaf water status, and chlorophyll content were assessed under three watering treatments. Results showed that effects of time, genotype, and treatment interact significantly in all traits. In addition, results confirmed that P. webbii have a greater tolerance to drought than commercial rootstocks. However, “Real Fino” apricot showed the fastest recovery after re-irrigation while being one of the most affected cultivars. In addition, from the better response to these watering treatments by the almond genotypes, two different trends were observed after re-irrigation treatment that clearly differentiate the response of the almond cultivar “Garrigue” from the rest of Prunus genotypes. A better characterization of the short-term drought response in Prunus, an accurate and more efficient evaluation of the genotype effect was obtained from the use of mixed models considering appropriate variance–covariance structures. Although the advantages of these approaches are rarely used in Prunus breeding, these methodologies should be undertaken in the future by breeders to increase efficiency in developing new breeding materials.
Lymphangioleiomyomatosis is a rare disorder of unknown origin that usually presents pulmonary symptoms. Retroperitoneal lymphangioleiomyomatosis without lung involvement has rarely been reported. We present a 38-year-old woman, the fourth case reported of retroperitoneal lymphangioleiomyomatosis with endosalpingiosis in the literature.
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