Rapid Phenotypic and Genotypic Diversification After Exposure to the Oral Host Niche in Candida albicans

Abstract

studies suggest that stress may generate random standing variation and that different cellular and ploidy states may evolve more rapidly under stress. Yet this idea has not been tested with pathogenic fungi growing within their host niche Here, we analyzed the generation of both genotypic and phenotypic diversity during exposure of to the mouse oral cavity. Ploidy, aneuploidy, loss of heterozygosity (LOH), and recombination were determined using flow cytometry and double digest restriction site-associated DNA sequencing. Colony phenotypic changes in size and filamentous growth were evident without selection and were enriched among colonies selected for LOH of the marker. Aneuploidy and LOH occurred on all chromosomes (Chrs), with aneuploidy more frequent for smaller Chrs and whole Chr LOH more frequent for larger Chrs. Large genome shifts in ploidy to haploidy often maintained one or more heterozygous disomic Chrs, consistent with random Chr missegregation events. Most isolates displayed several different types of genomic changes, suggesting that the oral environment rapidly generates diversity In sharp contrast, following propagation, isolates were not enriched for multiple LOH events, except in those that underwent haploidization and/or had high levels of Chr loss. The frequency of events was overall 100 times higher for populations following passage compared with These hyper-diverse isolates likely provide with the ability to adapt rapidly to the diversity of stress environments it encounters inside the host.

Aneuploidy in yeast: Segregation error or adaptation mechanism?

“…There have also been references to this pattern in studies of C. albicans (Forche et al, 2018) and C. neoformans var. grubii (Rhodes et al, 2017).…”

Role of homologous recombination genesRAD51,RAD52, andRAD59in the repair of lesions caused by γ-radiation to cycling and G2/M-arrested cells ofCandida albicans

“…It should be finally noticed that, as shown for some of them, a number of rad51 and rad52 survivors could have arisen by CT followed by addition of a telomere (Andaluz et al, 2011). (Selmecki et al, 2008), in immunocompromised patients treated with fluconazole (Ford et al, 2015), and during experimental oral infection in mice (Forche et al, 2018), it is not unexpected that following radiotherapy, some C. albicans survivors acquire new traits affecting drug-resistance and host adaptation. Evaluation of some of these traits in IR survivors carrying CA is in progress.…”

“…Part of the SSBs, either unprocessed or following resection and transformation into gaps, are likely repaired by nucleotide excision repair, but a significant fraction is rescued by HR, because HR mutants exhibit high susceptibility to UV light in both S. cerevisiae (Covo, Westmoreland, Gordenin, & Resnick, 2010;Ma, Westmoreland, & Resnick, 2013) and C. albicans (Ciudad et al, 2004;Garcia-Prieto et al, 2010;Legrand, Chan, Jauert, & Kirkpatrick, 2007). (Selmecki et al, 2008), in immunocompromised patients treated with fluconazole (Ford et al, 2015), and during experimental oral infection in mice (Forche et al, 2018), it is not unexpected that following radiotherapy, some C. albicans survivors acquire new traits affecting drug-resistance and host adaptation. It should be finally noticed that, as shown for some of them, a number of rad51 and rad52 survivors could have arisen by CT followed by addition of a telomere (Andaluz et al, 2011).…”

“…Repair of the lesions can generate large-scale genomic alterations, such as loss of heterozygosity (LOH) and aneuploidies, some of which might affect interaction between the fungus and the host (Bennett, Forche, & Berman, 2014;Bouchonville, Forche, Tang, Selmecki, & Berman, 2009;Forche, 2014;Ford et al, 2015;Rustchenko, 2007) allowing the former to rapidly adapt to the new niches and to cope with new stresses (Forche et al, 2018). For instance, it is not clear to which extent IR affect C. albicans genome or whether the infringed lesions are deleterious to the fungus or may eventually enhance its pathogenic potential.…”

“…For instance, it is not clear to which extent IR affect C. albicans genome or whether the infringed lesions are deleterious to the fungus or may eventually enhance its pathogenic potential. Repair of the lesions can generate large-scale genomic alterations, such as loss of heterozygosity (LOH) and aneuploidies, some of which might affect interaction between the fungus and the host (Bennett, Forche, & Berman, 2014;Bouchonville, Forche, Tang, Selmecki, & Berman, 2009;Forche, 2014;Ford et al, 2015;Rustchenko, 2007) allowing the former to rapidly adapt to the new niches and to cope with new stresses (Forche et al, 2018). Importantly, LOH and aneuploidy have been shown to affect several C. albicans phenotypes including filamentation, switching, biofilm formation, and resistance to antifungals, which are considered virulence factors (Bennett et al, 2014;Forche et al, 2011;Forche, Steinbach, & Berman, 2009;Ford et al, 2015;Selmecki, Dulmage, Cowen, Anderson, & Berman, 2009;Selmecki, Gerami-Nejad, Paulson, Forche, & Berman, 2008).…”