ACoccidioides posadasii CPS1Deletion Mutant Is Avirulent and Protects Mice from Lethal Infection
TheCPS1gene was identified as a virulence factor in the maize pathogenCochliobolus heterostrophus. Hypothesizing that the homologous gene inCoccidioides posadasiicould be important for virulence, we created a Δcps1deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,γcnull[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 × 107spores) 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 ofCPS1in virulence is not understood, phenotypic alterations and transcription differences of at least 33 genes in the Δcps1strain versusC. posadasiiis consistent with both metabolic and regulatory functions for the gene. Thein vitrophenotype of the Δcps1strain showed slower growth of mycelia with delayed and lower spore production thanC. posadasii, andin vitrospherules were smaller. Vaccination of C57BL/6 or BALB/c mice with live Δcps1spores either intranasally, intraperitoneally, or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens of <1,000 CFU from an otherwise lethalC. posadasiiintranasal infection. Considering its apparently complete attenuation of virulence and the high degree of resistance toC. posadasiiinfection when used as a vaccine, the Δcps1strain is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals.