Comparative analysis of pathogenicity of Cryptococcus neoformans serotypes A,D and AD in murine cryptococcosis

Objectives. To characterize the pathogenicity of 15 strains of Cryptococcus neoformans belonging to several serotype/mating type allele patterns (Dα, Da, Aα, Aa, Aα/Da and Dα/Aa) in experimental models of murine cryptococcosis. Methods. CD1-infected mice were examined for survival and fungal loads in either brain or lung during the course of infection. Results. All strains, with the exception of one Da strain, produced melanin in vitro. Similarly, all strains were encapsulated and produced phospholipase. When CD1 mice were challenged intravenously (i.v.) with 5×105 CFU/mouse and observed for 60 days post-infection, a significant variation of mortality rate was observed among mice infected with different strains. Aα and Aα/Da strains all produced 100% mortality within the study period with mean survivals significantly shorter than those of mice infected with strains belonging to any other allele type (P<0.0001). A wide range of pathogenicity was shown by haploid and diploid strains presenting Dα allele. This finding was confirmed by an intranasal model of challenge. To investigate the progression of infection, the mice were challenged i.v. with 5×104 CFU/mouse and tissue burden experiments (brain and lung) were performed on days 6 and 12 post-infection. Only the mice infected with Aα and Aα/Da strains showed a >1 log10 increase of CFU/g in both tissues throughout the study period. Conclusions. Our results suggest that the presence of the Aα mating type allele in either haploid or diploid strains is correlated with virulence, while the presence of the Aa or Da allele in haploid strains is associated with moderate or no virulence. Finally, either haploid or diploid strains presenting Dα allele vary in virulence.