title: Polyploid titan cells produce haploid and aneuploid progeny to promote stress adaptation.
abstract: Cryptococcus neoformans is a major life-threatening fungal pathogen. In response to the stress of the host environment, C. neoformans produces large polyploid titan cells. Titan cell production enhances the virulence of C. neoformans, yet whether the polyploid aspect of titan cells is specifically influential remains unknown. We show that titan cells were more likely to survive and produce offspring under multiple stress conditions than typical cells and that even their normally sized daughters maintained an advantage over typical cells in continued exposure to stress. Although polyploid titan cells generated haploid daughter cell progeny upon in vitro replication under nutrient-replete conditions, titan cells treated with the antifungal drug fluconazole produced fluconazole-resistant diploid and aneuploid daughter cells. Interestingly, a single titan mother cell was capable of generating multiple types of aneuploid daughter cells. The increased survival and genomic diversity of titan cell progeny promote rapid adaptation to new or high-stress conditions.
  
  
  OBJECTIVE
  The ability to adapt to stress is a key element for survival of pathogenic microbes in the host and thus plays an important role in pathogenesis. Here we investigated the predominantly haploid human fungal pathogen Cryptococcus neoformans, which is capable of ploidy and cell size increases during infection through production of titan cells. The enlarged polyploid titan cells are then able to rapidly undergo ploidy reduction to generate progeny with reduced ploidy and/or aneuploidy. Under stressful conditions, titan cell progeny have a growth and survival advantage over typical cell progeny. Understanding how titan cells enhance the rate of cryptococcal adaptation under stress conditions may assist in the development of novel drugs aimed at blocking ploidy transitions.
authors.affiliation: Department of Microbiology and Immunology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel Department of Genetics, Cell Biology & Development, College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Aleeza C
authors.initials: AC
authors.lastname: Gerstein
authors.affiliation: Department of Microbiology and Immunology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Man Shun
authors.initials: MS
authors.lastname: Fu
authors.affiliation: Department of Microbiology and Immunology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Liliane
authors.initials: L
authors.lastname: Mukaremera
authors.affiliation: Department of Microbiology and Immunology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Li
authors.affiliation: Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Ormerod
authors.affiliation: Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Fraser
authors.affiliation: Department of Microbiology and Immunology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel Department of Genetics, Cell Biology & Development, College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Berman
authors.affiliation: Department of Microbiology and Immunology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA knielsen@umn.edu.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Nielsen
mesh_terms: D000782:Aneuploidy; D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism; D003453:Cryptococcosis / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000502:physiology*; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D005260:Female; D015725:Fluconazole / Q000378:metabolism; D006238:Haploidy; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D011123:Polyploidy; D013312:Stress, Physiological
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole