Activation of Meiotic Genes Mediates Ploidy Reduction 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 large polyploid cells that exhibit increased resistance to host immune attack and are proposed to contribute to the latency of cryptococcal infection. These polyploid titan cells can generate haploid and aneuploid progeny that may result in systemic 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. Cryptococcal cells that activated their meiotic genes in mice were resistant to specific genotoxic stress compared to 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 their conventional roles in classic sexual reproduction, contribute to adaptation of eukaryotic cells that undergo dramatic genome changes in response to genotoxic stress. The discovery has additional implications 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 the polyploidization and meiosis-like ploidy reduction process in cancer cells, suggesting that the reversible ploidy change itself could provide a general mechanism for rejuvenation to promote individual survival in response to stress.