Candida albicans IRS4 contributes to hyphal formation and virulence after the initial stages of disseminated candidiasis

Abstract

Candida albicansis a common cause of mucosal and bloodstream infections. As a screening strategy to identify novel candidal virulence factors, sera recovered from HIV-infected patients with active oropharyngeal candidiasis (OPC) were previously used to probe aC. albicansgenomic expression library.IRS4was identified as a gene that encodes an immunogenic protein. In the present study, the presence ofIRS4transcripts was verified within OPC pseudomembranes recovered from patients. Having confirmed that the gene is expressed during human candidiasis, gene disruption strains were created and this implicatedIRS4in diverse processes, including hyphal formation on solid media and under embedded conditions, cell wall integrity and structure, and adherence to human epithelial cellsin vitro.IRS4disruption, however, did not influence hyphal formation or virulence in a murine model of OPC. Rather, the gene was found to be necessary for normal morphogenesis and full virulence during murine intravenously disseminated candidiasis (DC).IRS4's effects on hyphal formation and virulence during DC were not evident on the first day after intravenous inoculation, even though transcripts were detected within murine kidneys. After 4 days, however, anirs4null mutant strain was associated with attenuated mortality, diminished tissue burdens, less extensive infections, impairedC. albicanshyphal formation and decreased kidney damage. Taken together, these findings suggest thatIRS4makes distinct temporal-spatial contributions to the pathogenesis of candidiasis, which appear to vary between different tissue sites as well as within a given tissue over time.