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.

Titan cell production in Cryptococcus neoformans reshapes the cell wall and capsule composition during infection

“…To separate titan and normal-sized (which we refer to as “typical”) cell populations, we used a previously described method (Gerstein et al, 2015). As previously, C. neoformans cells (mixture of titan and typical cells) from lung homogenates were filtered using CellMicroSieves (BioDesign Inc. of New York, Carmel, NY) with a 20-µm pore size that allows typical cells to pass through the membrane.…”

Cryptococcus: from environmental saprophyte to global pathogen

“…This polysaccharide is recognized and cleaved by host chitinases, which induces a detrimental adaptive immune response (see below) 17 . Intriguingly, the polyploidy observed in titan cells enhances genetic adaptation to the stressful host environment, resulting in increased within-host survival 18 .…”

Physiological Differences in Cryptococcus neoformans Strains In Vitro versus In Vivo and Their Effects on Antifungal Susceptibility

“…Titan cells are significantly less susceptible to high concentrations of FLC than are typical cells (52). Perhaps more interesting, given titan cells' possible role in seeding the host with more readily disseminated daughter cells, is the fact that typically sized progeny of titan cells grown in the presence of FLC were significantly more likely to survive and propagate in FLC than the progeny of typically sized cells grown under the same conditions (52).…”

“…Perhaps more interesting, given titan cells' possible role in seeding the host with more readily disseminated daughter cells, is the fact that typically sized progeny of titan cells grown in the presence of FLC were significantly more likely to survive and propagate in FLC than the progeny of typically sized cells grown under the same conditions (52). Almost all (97.9%) strains derived from daughters of FLC-stressed titan cells were found to contain extra copies of entire (95.8%) or partial (2.1%) chromosomes on top of their background, which was usually haploid, with a notable minority (25%) of diploids (52). This was in contrast to the offspring of titan cells grown without FLC, which were haploid and apparently typical.…”

“…Though titan cells are believed to be too large to disseminate from the lung to the brain, their production greatly increases the dissemination of typical cells to the CNS (48). This has been hypothesized to occur either by inducing a Th2-driven response that less effectively combats the infection or by the production of haploid daughter cells, which have been shown to be more resistant to various kinds of stress, including those encountered within macrophages (48,52).…”