title: A Coccidioides posadasii CPS1 Deletion Mutant Is Avirulent and Protects Mice from Lethal Infection.
abstract: The CPS1 gene was identified as a virulence factor in the maize pathogen Cochliobolus heterostrophus Hypothesizing that the homologous gene in Coccidioides posadasii could be important for virulence, we created a Δcps1 deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,γc(null) [NSG]). Only a single colony was recovered from 1 of 60 C57BL/6 mice following intranasal infections of up to 4,400 spores. Following administration of very high doses (10,000 to 2.5 × 10(7) spores) to NSG and BALB/c mice, spherules were observed in lung sections at time points from day 3 to day 10 postinfection, but nearly all appeared degraded with infrequent endosporulation. Although the role of CPS1 in virulence is not understood, phenotypic alterations and transcription differences of at least 33 genes in the Δcps1 strain versus C. posadasii is consistent with both metabolic and regulatory functions for the gene. The in vitro phenotype of the Δcps1 strain showed slower growth of mycelia with delayed and lower spore production than C. posadasii, and in vitro spherules were smaller. Vaccination of C57BL/6 or BALB/c mice with live Δcps1 spores either intranasally, intraperitoneally, or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens of <1,000 CFU from an otherwise lethal C. posadasii intranasal infection. Considering its apparently complete attenuation of virulence and the high degree of resistance to C. posadasii infection when used as a vaccine, the Δcps1 strain is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals.
authors.affiliation: School of Plant Sciences, The University of Arizona, Tucson, Arizona, USA.
authors.forename: Hema P
authors.initials: HP
authors.lastname: Narra
authors.affiliation: School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA The Valley Fever Center for Excellence, The University of Arizona, Tucson, Arizona, USA.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Shubitz
authors.affiliation: School of Plant Sciences, The University of Arizona, Tucson, Arizona, USA The Valley Fever Center for Excellence, The University of Arizona, Tucson, Arizona, USA.
authors.forename: M Alejandra
authors.initials: MA
authors.lastname: Mandel
authors.affiliation: School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA The Valley Fever Center for Excellence, The University of Arizona, Tucson, Arizona, USA.
authors.forename: Hien T
authors.initials: HT
authors.lastname: Trinh
authors.affiliation: Department of Immunobiology, The University of Arizona, Tucson, Arizona, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Griffin
authors.affiliation: Department of Immunobiology, The University of Arizona, Tucson, Arizona, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Buntzman
authors.affiliation: The Valley Fever Center for Excellence, The University of Arizona, Tucson, Arizona, USA Department of Immunobiology, The University of Arizona, Tucson, Arizona, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Frelinger
authors.affiliation: The Valley Fever Center for Excellence, The University of Arizona, Tucson, Arizona, USA Department of Medicine, The University of Arizona, Tucson, Arizona, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Galgiani
authors.affiliation: School of Plant Sciences, The University of Arizona, Tucson, Arizona, USA The Valley Fever Center for Excellence, The University of Arizona, Tucson, Arizona, USA orbachmj@email.arizona.edu.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Orbach
mesh_terms: D000818:Animals; D003045:Coccidioides / Q000235:genetics / Q000502:physiology*; D003047:Coccidioidomycosis / Q000235:genetics* / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D017384:Sequence Deletion; D014611:Vaccination / Q000379:methods; D014774:Virulence / Q000502:physiology*; D037521:Virulence Factors / Q000235:genetics*
chemical_list: D005656:Fungal Proteins; D037521:Virulence Factors