المؤلفون: Szebenyi, Csilla, Gu, Yiyou, Gebremariam, Teclegiorgis, Kocsubé, Sándor, Kiss-Vetráb, Sándor, Jáger, Olivér, Patai, Roland, Spisák, Krisztina, Sinka, Rita, Binder, Ulrike, Homa, Mónika, Vágvölgyi, Csaba, Ibrahim, Ashraf S, Nagy, Gábor, Papp, Tamás

المصدر: mBio. 14(1)

مصطلحات موضوعية: Emerging Infectious Diseases, Infectious Diseases, Genetics, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Aetiology, Infection, Animals, Mice, Humans, Mucor, Mucormycosis, Virulence, Mucorales, Spores, mucormycosis, virulence factor, spore coat protein, CRISPR-Cas9, CotH, Drosophila melanogaster, Galleria mellonella, mice, Mucor lusitanicus, chitin, pathogenesis, virulence determinants, Microbiology

الوصف: Mucormycosis is an invasive fungal infection caused by certain members of the fungal order of Mucorales. The species most frequently identified as the etiological agents of mucormycosis belong to the genera Rhizopus, Lichtheimia, and Mucor. The frequency of systemic mucormycosis has been increasing, mainly because of increasing numbers of susceptible patients. Furthermore, Mucorales display intrinsic resistance to the majority of routinely used antifungal agents (e.g., echinocandins and short-tailed azoles), which limits the number of possible therapeutic options. All the above-mentioned issues urge the improvement of molecular identification methods and the discovery of new antifungal targets and strategies. Spore coat proteins (CotH) constitute a kinase family present in many pathogenic bacteria and fungi and participate in the spore formation in these organisms. Moreover, some of them can act as virulence factors being receptors of the human GRP78 protein during Rhizopus delemar-induced mucormycosis. We identified 17 cotH-like genes in the Mucor lusitanicus genome database. Successful disruption of five cotH genes in Mucor was performed using the CRISPR-Cas9 system. The CotH3 and CotH4 proteins play a role in adaptation to different temperatures as well as in developing the cell wall structure. We also show CotH4 protein is involved in spore wall formation by affecting the total chitin content and, thus, the composition of the spore wall. The role of CotH3 and CotH4 proteins in virulence was confirmed in two invertebrate models and a diabetic ketoacidosis (DKA) mouse model. IMPORTANCE Current treatment options for mucormycosis are inadequate, resulting in high mortality rates, especially among immunosuppressed patients. The development of novel therapies for mucormycosis has been hampered by lack of understanding of the pathogenetic mechanisms. The importance of the cell surface CotH proteins in the pathogenesis of Rhizopus-mediated mucormycosis has been recently described. However, the contribution of this family of proteins to the virulence of other mucoralean fungi and their functionality in vital processes remain undefined. Through the use of the CRISPR-Case9 gene disruption system, we demonstrate the importance of several of the CotH proteins to the virulence of Mucor lusitanicus by using three infection models. We also report on the importance of one of these proteins, CotH4, to spore wall formation by affecting chitin content. Therefore, our studies extend the importance of CotH proteins to Mucor and identify the mechanism by which one of the CotH proteins contributes to the development of a normal fungal cell wall, thereby indicating that this family of proteins can be targeted for future development of novel therapeutic strategies of mucormycosis.

وصف الملف: application/pdf

URL الوصول: https://escholarship.org/uc/item/8d65b48m

المؤلفون: Varga, Torda, Krizsán, Krisztina, Földi, Csenge, Dima, Bálint, Sánchez-García, Marisol, Sánchez-Ramírez, Santiago, Szöllősi, Gergely J, Szarkándi, János G, Papp, Viktor, Albert, László, Andreopoulos, William, Angelini, Claudio, Antonín, Vladimír, Barry, Kerrie W, Bougher, Neale L, Buchanan, Peter, Buyck, Bart, Bense, Viktória, Catcheside, Pam, Chovatia, Mansi, Cooper, Jerry, Dämon, Wolfgang, Desjardin, Dennis, Finy, Péter, Geml, József, Haridas, Sajeet, Hughes, Karen, Justo, Alfredo, Karasiński, Dariusz, Kautmanova, Ivona, Kiss, Brigitta, Kocsubé, Sándor, Kotiranta, Heikki, LaButti, Kurt M, Lechner, Bernardo E, Liimatainen, Kare, Lipzen, Anna, Lukács, Zoltán, Mihaltcheva, Sirma, Morgado, Louis N, Niskanen, Tuula, Noordeloos, Machiel E, Ohm, Robin A, Ortiz-Santana, Beatriz, Ovrebo, Clark, Rácz, Nikolett, Riley, Robert, Savchenko, Anton, Shiryaev, Anton, Soop, Karl, Spirin, Viacheslav, Szebenyi, Csilla, Tomšovský, Michal, Tulloss, Rodham E, Uehling, Jessie, Grigoriev, Igor V, Vágvölgyi, Csaba, Papp, Tamás, Martin, Francis M, Miettinen, Otto, Hibbett, David S, Nagy, László G

المصدر: Nature Ecology & Evolution. 3(4)

مصطلحات موضوعية: Biological Sciences, Ecology, Evolutionary Biology, Agaricales, Genetic Variation, Genome, Fungal, Phylogeny, Evolutionary biology, Environmental management

الوصف: Mushroom-forming fungi (Agaricomycetes) have the greatest morphological diversity and complexity of any group of fungi. They have radiated into most niches and fulfil diverse roles in the ecosystem, including wood decomposers, pathogens or mycorrhizal mutualists. Despite the importance of mushroom-forming fungi, large-scale patterns of their evolutionary history are poorly known, in part due to the lack of a comprehensive and dated molecular phylogeny. Here, using multigene and genome-based data, we assemble a 5,284-species phylogenetic tree and infer ages and broad patterns of speciation/extinction and morphological innovation in mushroom-forming fungi. Agaricomycetes started a rapid class-wide radiation in the Jurassic, coinciding with the spread of (sub)tropical coniferous forests and a warming climate. A possible mass extinction, several clade-specific adaptive radiations and morphological diversification of fruiting bodies followed during the Cretaceous and the Paleogene, convergently giving rise to the classic toadstool morphology, with a cap, stalk and gills (pileate-stipitate morphology). This morphology is associated with increased rates of lineage diversification, suggesting it represents a key innovation in the evolution of mushroom-forming fungi. The increase in mushroom diversity started during the Mesozoic-Cenozoic radiation event, an era of humid climate when terrestrial communities dominated by gymnosperms and reptiles were also expanding.

وصف الملف: application/pdf

URL الوصول: https://escholarship.org/uc/item/0tx3k9hc

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