Cryptococcus neoformans STE12α regulates virulence but is not essential for mating

The Cryptococcus neoformans STE12 alpha gene, a homologue of Saccharomyces cerevisiae STE12, exists only in mating type (MAT)alpha cells. In S. cerevisiae, STE12 was required for mating and filament formation. In C. neoformans, haploid fruiting on filament agar required STE12 alpha. The ability to form hyphae, however, was not affected by deletion of STE12 alpha when convergently growing MATa strains were present. Furthermore, ste12 alpha disruptants were fertile when mated with MATa strains, albeit with reduced mating frequency. Most importantly, the virulence of a ste12 alpha disruptant of serotype D strain was significantly reduced in a mouse model. When the ste12 alpha locus was reconstituted with the wild-type allele by cotransformation, virulence was restored. Histopathological analysis demonstrated a reduction in capsular size of yeast cells, less severe cystic lesions, and stronger immune responses in meninges of mice mice infected with ste12 alpha cells than those of mice infected with STE12 alpha cells. Using reporter gene constructs, we found that STE12 alpha controls the expression of several phenotypes known to be involved in virulence, such as capsule and melanin production. These results demonstrate a clear molecular link between mating type and virulence in C. neoformans.