title: Distinct Roles of Myosins in Aspergillus fumigatus Hyphal Growth and Pathogenesis.
abstract: Myosins are a family of actin-based motor proteins found in many organisms and are categorized into classes based on their structures. Class II and V myosins are known to be important for critical cellular processes, including cytokinesis, endocytosis, exocytosis, and organelle trafficking, in the model fungi Saccharomyces cerevisiae and Aspergillus nidulans However, the roles of myosins in the growth and virulence of the pathogen Aspergillus fumigatus are unknown. We constructed single- and double-deletion strains of the class II and class V myosins in A. fumigatus and found that while the class II myosin (myoB) is dispensable for growth, the class V myosin (myoE) is required for proper hyphal extension; deletion of myoE resulted in hyperbranching and loss of hyphal polarity. Both myoB and myoE are necessary for proper septation, conidiation, and conidial germination, but only myoB is required for conidial viability. Infection with the ΔmyoE strain in the invertebrate Galleria mellonella model and also in a persistently immunosuppressed murine model of invasive aspergillosis resulted in hypovirulence, while analysis of bronchoalveolar lavage fluid revealed that tumor necrosis factor alpha (TNF-α) release and cellular infiltration were similar compared to those of the wild-type strain. The ΔmyoE strain showed fungal growth in the murine lung, while the ΔmyoB strain exhibited little fungal burden, most likely due to the reduced conidial viability. These results show, for the first time, the important role these cytoskeletal components play in the growth of and disease caused by a known pathogen, prompting future studies to understand their regulation and potential targeting for novel antifungal therapies.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Renshaw
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: José M
authors.initials: JM
authors.lastname: Vargas-Muñiz
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Amber D
authors.initials: AD
authors.lastname: Richards
authors.affiliation: Division of Laboratory Animal Resources, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Yohannes G
authors.initials: YG
authors.lastname: Asfaw
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Praveen R
authors.initials: PR
authors.lastname: Juvvadi
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA bill.steinbach@duke.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Steinbach
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000382:microbiology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity*; D015169:Colony Count, Microbial; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D025301:Hyphae / Q000254:growth & development*; D008168:Lung / Q000382:microbiology; D008297:Male; D051379:Mice; D050296:Microbial Viability; D009218:Myosins / Q000172:deficiency / Q000378:metabolism*; D013172:Spores, Fungal / Q000254:growth & development; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D009218:Myosins