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Cryptococcus neoformansis a common cause of meningoencephalitis among AIDS patients. SeveralC. neoformansvirulence factors have been identified, but the relative importance of particular factors is unknown. This study examined the corrrelation of the virulence of 18C. neoformansvar.grubiiisolates from AIDS patients with the expression of several well-described virulence factors. The LD50at 15 days after intracranial inoculation of ICR mice was 20 000 for 39 %. Higher cryptococcal concentrations in brains were noted for isolates with lower LD50(P=0.002). In survival studies, no immunocompetent BALB/c mice (nu/−) infected with 3×LD50of three virulent isolates (LD50=62, 99, 1280) survived beyond 23 days, whereas 100 %, 90 % and 90 % of mice infected with 20 000 c.f.u. of three hypovirulent isolates (LD50>20 000) survived for 60 days (Pnu/nu) mice, survival rates over 60 days were 100 %, 70 % and 50 %, respectively, for the hypovirulent isolates. Growth rate at 37 °C and capsule size within brains correlated with LD50by univariate (P=0.0001 and 0.028, respectively) and multivariate (P=0.017 and 0.016, respectively) analyses. There was no correlation between LD50and capsule sizein vitro, phospholipase activity, melanin formation, proteinase activity and fluconazole MIC. In conclusion, AIDS patients are susceptible to infection byC. neoformansisolates of wide-ranging virulence, including isolates that are markedly hypovirulent. The virulence of a given isolate reflects a composite of factors rather than the contribution of a dominant factor. Growth at 37 °C and capsule sizein vivomake particularly important contributions.

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.