Heterotrimeric G-alpha subunits Gpa11 and Gpa12 define a transduction pathway that control spore size and virulence in Mucor circinelloides

Autoři: J. Alberto Patiño-Medina aff001;  Nancy Y. Reyes-Mares aff001;  Marco I. Valle-Maldonado aff001;  Irvin E. Jácome-Galarza aff002;  Carlos Pérez-Arques aff003;  Rosa E. Nuñez-Anita aff004;  Jesús Campos-García aff001;  Verónica Anaya-Martínez aff005;  Rafael Ortiz-Alvarado aff006;  Martha I. Ramírez-Díaz aff001;  Soo Chan Lee aff007;  Victoriano Garre aff003;  Víctor Meza-Carmen aff001
Působiště autorů: Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo (UMSNH), Morelia, Michoacán, México aff001;  Departamento de Biología Molecular, Laboratorio Estatal de Salud Pública del Estado de Michoacán, Morelia, Michoacán, México aff002;  Departamento de Genética y Microbiología, Facultad de Biología, Universidad de Murcia, Murcia, España aff003;  Facultad de Medicina Veterinaria y Zootecnia, Universidad Michoacana de San Nicolás Hidalgo, Morelia, Michoacán, Mexico aff004;  Facultad de Ciencias de la Salud, Universidad Anáhuac, Naucalpan de Juarez, Estado de México, México aff005;  Facultad de Químico Farmacobiología, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacan, México aff006;  Department of Biology, South Texas Center of Emerging Infectious Diseases (STCEID), University of Texas at San Antonio, San Antonio, Texas, United States of America aff007
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226682


Mucor circinelloides is one of the causal agents of mucormycosis, an emerging and high mortality rate fungal infection produced by asexual spores (sporangiospores) of fungi that belong to the order Mucorales. M. circinelloides has served as a model genetic system to understand the virulence mechanism of this infection. Although the G-protein signaling cascade plays crucial roles in virulence in many pathogenic fungi, its roles in Mucorales are yet to be elucidated. Previous study found that sporangiospore size and calcineurin are related to the virulence in Mucor, in which larger spores are more virulent in an animal mucormycosis model and loss of a calcineurin A catalytic subunit CnaA results in larger spore production and virulent phenotype. The M. circinelloides genome is known to harbor twelve gpa (gpa1 to gpa12) encoding G-protein alpha subunits and the transcripts of the gpa11 and gpa12 comprise nearly 72% of all twelve gpa genes transcript in spores. In this study we demonstrated that loss of function of Gpa11 and Gpa12 led to larger spore size associated with reduced activation of the calcineurin pathway. Interestingly, we found lower levels of the cnaA mRNAs in sporangiospores from the Δgpa12 and double Δgpa11gpa12 mutant strains compared to wild-type and the ΔcnaA mutant had significantly lower gpa11 and gpa12 mRNA levels compared to wild-type. However, in contrast to the high virulence showed by the large spores of ΔcnaA, the spores from Δgpa11gpa12 were avirulent and produced lower tissue invasion and cellular damage, suggesting that the gpa11 and gpa12 define a signal pathway with two branches. One of the branches controls spore size through regulation of calcineurin pathway, whereas virulences is controlled by an independent pathway. This virulence-related regulatory pathway could control the expression of genes involved in cellular responses important for virulence, since sporangiospores of Δgpa11gpa12 were less resistant to oxidative stress and phagocytosis by macrophages than the ΔcnaA and wild-type strains. The characterization of this pathway could contribute to decipher the signals and mechanism used by Mucorales to produce mucormycosis.

Klíčová slova:

Fungal genetics – Fungal spores – Gene expression – Macrophages – Mutant strains – Oligonucleotides – Polymerase chain reaction – Fungal spore germination


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