Jul 22, 2016 - 2- to 4-m arthroconidium (spore) initiates a respiratory infec- tion and grows as a unique parasitic phase structure, the spherule, to 80 to 100 m ...
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A Coccidioides posadasii CPS1 Deletion Mutant Is Avirulent and Protects Mice from Lethal Infection Hema P. Narra,a* Lisa F. Shubitz,b,c M. Alejandra Mandel,a,c Hien T. Trinh,b,c Kurt Griffin,d* Adam S. Buntzman,d* Jeffrey A. Frelinger,c,d John N. Galgiani,c,e Marc J. Orbacha,c School of Plant Sciences,a School of Animal and Comparative Biomedical Sciences,b The Valley Fever Center for Excellence,c Department of Immunobiology,d and Department of Medicine,e The University of Arizona, Tucson, Arizona, USA
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 ⌬cps1 deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,␥cnull [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 ⴛ 107 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 ⌬cps1 strain versus C. posadasii is consistent with both metabolic and regulatory functions for the gene. The in vitro phenotype of the ⌬cps1 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 ⌬cps1 spores either intranasally, intraperitoneally, or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens of
