Activation of Meiotic Genes Mediates Ploidy Reduction and Generates Phenotypic Diversity During Cryptococcal Infection

Cryptococcus neoformans is a global human fungal pathogen that causes fatal meningoencephalitis in mostly immunocompromised individuals. During pulmonary infection, cryptococcal cells form big polyploid cells that exhibit increased resistance to host immune attack and are proposed to contribute to the latency of cryptococcal infection. These polyploidy titan cells can generate haploid and aneuploid progeny that may result in systematic infection. What triggers cryptococcal polyploidization and how ploidy reduction is achieved remain open questions. Here we discovered that Cryptococcus cells polyploidize in response to genotoxic stresses that cause DNA double strand breaks. Intriguingly, meiosis-specific genes are activated in C. neoformans and contribute to ploidy reduction, both in vitro and during infection in mice. Strikingly, cryptococcal cells that activated their meiotic genes in mice showed increased phenotypic diversity and were resistant to specific genotoxic stress comparing with sister cells recovered from the same host tissue but without activation of meiotic genes. Our findings support the idea that meiotic genes, in addition to the conventional roles during classic sexual reproduction, contribute to adaptation of eukaryotic cells undergoing dramatic genome changes in response to genotoxic stress. The discovery has additional implication for evolution of sexual reproduction and the paradox of the presence of meiotic machinery in asexual species. Finally, our findings in this eukaryotic microbe mirror the revolutionary discoveries of gametogenesis (polyploidization and meiosis-like process) in cancer cells, suggesting that the gametogenesis process itself could provide a general mechanism for rejuvenation in response to stress to promote individual survival.