Host-Induced Genome Instability Rapidly Generates Phenotypic Variation across Candida albicans Strains and Ploidy States
Host-Induced Genome Instability Rapidly Generates Phenotypic Variation across Candida albicans Strains and Ploidy States
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DOI：
10.1128/msphere.00433-20
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发表时间：
2020-06
期刊：
影响因子：
4.8
通讯作者：
Amanda C. Smith;Meleah A. Hickman
中科院分区：
文献类型：
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作者：
Amanda C. Smith;Meleah A. Hickman
白色念珠菌是人类的机会性真菌病原体。产生遗传变异的能力对于适应是必不可少的，也是白色念珠菌和其他真菌病原体用来改变其基因组大小的一种策略。压力环境，包括宿主，诱导白色念珠菌基因组不稳定。在这里，我们研究了体外和宿主环境下白色念珠菌的遗传背景和倍性状态如何影响基因组的不稳定性。我们发现宿主环境诱导基因组不稳定，但其程度取决于白色念珠菌的遗传背景。此外，我们发现四倍体白色念珠菌在宿主环境中高度不稳定，并且基因组大小迅速减少。这些基因组大小的减少往往导致毒性的降低。相比之下，二倍体白色念珠菌表现出适度的宿主诱导的基因组大小变化，但这些变化经常导致毒性增加。这样的研究对于了解机会致病菌如何对宿主环境作出反应和潜在的适应至关重要。白色念珠菌是一种典型的二倍体人类机会性真菌病原体，但具有高度不稳定的基因组，可耐受大规模扰动，包括染色体非整倍体和杂合性丧失事件。快速产生遗传变异的能力对于白色念珠菌适应不断变化或压力的环境至关重要，就像在宿主中遇到的那样。遗传变异可以通过胁迫诱导的诱变产生，也可以通过其拟性循环产生，其中四倍体通过二倍体交配或胁迫诱导的有丝分裂缺陷产生，并经历非减数分裂倍体减少。然而，在体外或宿主环境中，遗传背景如何导致白色念珠菌基因组不稳定仍不得而知。在这里，我们测试了遗传背景、倍性和宿主环境如何影响白色念珠菌基因组的稳定性。我们发现，无论遗传背景或倍性如何，宿主关联都会诱导杂合性缺失事件和基因组大小变化。然而，基因组变化的幅度和类型因白色念珠菌菌株背景和倍性状态而异。然后，我们评估了宿主诱导的基因组变化是否会对生长速度和非致死性毒力表型产生适应性影响，并发现许多宿主衍生的分离株相对于其亲本菌株发生了显著变化。有趣的是，二倍体宿主相关的白色念珠菌主要降低宿主的生殖适应性，而四倍体宿主相关的白色念珠菌则增加宿主的生殖适应性。总之，这些结果对于理解宿主诱导的白色念珠菌基因组变化如何改变其与宿主的关系非常重要。白色念珠菌是人类的机会性真菌病原体。产生遗传变异的能力对于适应是必不可少的，也是白色念珠菌和其他真菌病原体用来改变其基因组大小的一种策略。压力环境，包括宿主，诱导白色念珠菌基因组不稳定。在这里，我们研究了体外和宿主环境下白色念珠菌的遗传背景和倍性状态如何影响基因组的不稳定性。我们发现宿主环境诱导基因组不稳定，但其程度取决于白色念珠菌的遗传背景。此外，我们发现四倍体白色念珠菌在宿主环境中高度不稳定，并且基因组大小迅速减少。这些基因组大小的减少往往导致毒性的降低。相比之下，二倍体白色念珠菌表现出适度的宿主诱导的基因组大小变化，但这些变化经常导致毒性增加。这样的研究对于了解机会致病菌如何对宿主环境作出反应和潜在的适应至关重要。
Candida albicans is an opportunistic fungal pathogen of humans. The ability to generate genetic variation is essential for adaptation and is a strategy that C. albicans and other fungal pathogens use to change their genome size. Stressful environments, including the host, induce C. albicans genome instability. Here, we investigated how C. albicans genetic background and ploidy state impact genome instability, both in vitro and in a host environment. We show that the host environment induces genome instability, but the magnitude depends on C. albicans genetic background. Furthermore, we show that tetraploid C. albicans is highly unstable in host environments and rapidly reduces in genome size. These reductions in genome size often resulted in reduced virulence. In contrast, diploid C. albicans displayed modest host-induced genome size changes, yet these frequently resulted in increased virulence. Such studies are essential for understanding how opportunistic pathogens respond and potentially adapt to the host environment. ABSTRACT Candida albicans is an opportunistic fungal pathogen of humans that is typically diploid yet has a highly labile genome tolerant of large-scale perturbations including chromosomal aneuploidy and loss-of-heterozygosity events. The ability to rapidly generate genetic variation is crucial for C. albicans to adapt to changing or stressful environments, like those encountered in the host. Genetic variation occurs via stress-induced mutagenesis or can be generated through its parasexual cycle, in which tetraploids arise via diploid mating or stress-induced mitotic defects and undergo nonmeiotic ploidy reduction. However, it remains largely unknown how genetic background contributes to C. albicans genome instability in vitro or in the host environment. Here, we tested how genetic background, ploidy, and the host environment impacts C. albicans genome stability. We found that host association induced both loss-of-heterozygosity events and genome size changes, regardless of genetic background or ploidy. However, the magnitude and types of genome changes varied across C. albicans strain background and ploidy state. We then assessed if host-induced genomic changes resulted in fitness consequences on growth rate and nonlethal virulence phenotypes and found that many host-derived isolates significantly changed relative to their parental strain. Interestingly, diploid host-associated C. albicans predominantly decreased host reproductive fitness, whereas tetraploid host-associated C. albicans increased host reproductive fitness. Together, these results are important for understanding how host-induced genomic changes in C. albicans alter its relationship with the host. IMPORTANCE Candida albicans is an opportunistic fungal pathogen of humans. The ability to generate genetic variation is essential for adaptation and is a strategy that C. albicans and other fungal pathogens use to change their genome size. Stressful environments, including the host, induce C. albicans genome instability. Here, we investigated how C. albicans genetic background and ploidy state impact genome instability, both in vitro and in a host environment. We show that the host environment induces genome instability, but the magnitude depends on C. albicans genetic background. Furthermore, we show that tetraploid C. albicans is highly unstable in host environments and rapidly reduces in genome size. These reductions in genome size often resulted in reduced virulence. In contrast, diploid C. albicans displayed modest host-induced genome size changes, yet these frequently resulted in increased virulence. Such studies are essential for understanding how opportunistic pathogens respond and potentially adapt to the host environment.