Impact of Mating Type, Serotype, and Ploidy on Virulence of Cryptococcus neoformans

Department of Molecular Genetics and Microbiology, Duke University Medical Center Durham, North Carolina, USA

^* To whom correspondence should be addressed. Email: heitm001{at}duke.edu.

	Abstract

Hybridization with polyploidization is a significant biological force driving evolution. The effect of combining two distinct genomes in one organism on the virulence potential of pathogenic fungi is not clear. Cryptococcus neoformans, the most common cause of fungal infection of the central nervous system, has a bipolar mating system with a and mating types and occurs as A (haploid), D (haploid), or AD hybrid (mostly diploid) serotypes. Diploid AD hybrids derive either from a- mating or from unisexual mating between haploid cells. The precise contributions of increased ploidy, the effect of hybridization between serotype A and D, and the combination of mating-type to the virulence potential of AD hybrids have remained elusive. By in vitro and in vivo characterization of laboratory-constructed isogenic diploids and AD hybrids with all possible mating-type combinations in defined genetic backgrounds, we found that higher ploidy has a minor negative effect on virulence in a murine inhalation model of cryptococcosis. The presence of both mating-type a and in AD hybrids did not affect the virulence potential, irrespective of their serotype origin. Interestingly, AD hybrids with only one mating type behaved differently with the virulence of AD strains similar to those of other hybrids while aADa hybrids displayed significantly lower virulence due to negative epistatic interactions between Aa and Da alleles of the mating type locus. This study provides insights on the impact of ploidy, mating type, and serotype on virulence, and the impact of hybridization on fitness and virulence of a eukaryotic microbial pathogen.