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Published on: October 11, 2022
Activation of Meiotic Genes Mediates Ploidy Reduction during Cryptococcal Infection
Youbao Zhao1, Yina Wang2, Srijana Upadhyay1
1Department of Microbiology, University of Georgia, Athens, GA 30602, USA.
Abstract:
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.
Insights
Cryptococcus neoformans cells polyploidize under genotoxic stress. Meiosis genes activate to reduce ploidy, enhancing survival and adaptation during infection, offering insights into eukaryotic cell stress responses.
Area of Science:
- Mycology
- Genetics
- Cell Biology
Background:
- Cryptococcus neoformans causes life-threatening meningoencephalitis, particularly in immunocompromised individuals.
- During infection, C. neoformans forms polyploid titan cells, increasing resistance to host immunity and potentially causing latent infections.
- The triggers for cryptococcal polyploidization and mechanisms for ploidy reduction remain largely unknown.
Purpose of the Study:
- To investigate the triggers of polyploidization in Cryptococcus neoformans.
- To elucidate the mechanisms underlying ploidy reduction in this fungal pathogen.
- To explore the role of meiotic genes in cryptococcal adaptation to stress.
Main Methods:
- Induction of genotoxic stress in Cryptococcus neoformans cultures.
- Analysis of gene expression, focusing on meiosis-specific genes.
- In vivo studies using a mouse model of cryptococcal infection.
- Comparison of stress resistance between cells with and without activated meiotic genes.
Main Results:
- Cryptococcus cells undergo polyploidization in response to genotoxic stress causing DNA double-strand breaks.
- Meiosis-specific genes are activated during polyploidization and contribute to ploidy reduction both in vitro and in vivo.
- Activated meiotic genes confer resistance to specific genotoxic stresses during infection in mice.
Conclusions:
- Meiotic genes in C. neoformans contribute to adaptation by facilitating ploidy reduction under genotoxic stress, beyond their role in sexual reproduction.
- This reversible ploidy change mechanism may be a general survival strategy for eukaryotic cells facing stress, mirroring processes observed in cancer cells.
- The findings have implications for understanding the evolution of sexual reproduction and the presence of meiotic machinery in asexual organisms.
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