Biology subjects

Hickman, M. A.

Publications and source records attributed to Hickman, M. A..

7 recordsLinked to original sources

bioRxiv2021

Host defense mechanisms induce genome instability in an opportunistic fungal pathogen

The ability to generate genetic variation facilitates rapid adaptation in stressful environments. The opportunistic fungal pathogen Candida albicans frequently undergoes large-scale genomic changes, including aneuploidy and loss-of heterozygosity (LOH), following exposure to physiological stressors and host environments. However, the specific host factors that induce C. albicans genome instability remains largely unknown. Here, we leveraged genetically-tractable nematode hosts to specifically investigate the innate immune components driving host-associated C. albicans genome instability, which include host production of antimicrobial peptides (AMPs) and reactive oxygen species (ROS). C. albicans associated with wildtype, immunocompetent hosts carried multiple large-scale genomic changes including LOH, whole chromosome, and segmental aneuploidies. In contrast, C. albicans associated with immunocompromised hosts deficient in AMPs or ROS production had reduced LOH frequencies and fewer, if any, additional genomic changes. We also found that C. albicans cap1{Delta}/{Delta} strains deficient in ROS detoxification, were more susceptible to host-produced ROS genome instability compared to wildtype C. albicans. Further, genomic perturbations resulting from host-produced ROS are mitigated by the addition of antioxidants. Taken together, this work suggests that host-produced ROS and AMPs induces genotypic plasticity in C. albicans which may facilitate rapid adaptation and lead to phenotypic changes.

genomics↗

bioRxiv2021

Tetraploidy accelerates adaptation under drug-selection in a fungal pathogen

Baseline ploidy significantly impacts evolutionary trajectories, and in particular, tetraploidy has been associated with higher rates of adaptation compared to haploidy and diploidy. While the majority of experimental evolution studies investigating ploidy use Saccharomyces cerivisiae, the fungal pathogen Candida albicans is a powerful system to investigate ploidy dynamics, particularly in the context of antifungal drug resistance. C. albicans laboratory and clinical strains are predominantly diploid, but have also been isolated as haploid and polyploid. Here, we evolved diploid and tetraploid C. albicans for [~]60 days in the antifungal drug caspofungin. Tetraploid-evolved lines adapted faster than diploid-evolved lines and reached higher levels of caspofungin resistance. While diploid-evolved lines generally maintained their initial genome size, tetraploid-evolved lines rapidly underwent genome-size reductions and did so prior to caspofungin adaption. Furthermore, fitness costs in the absence of drug selection were significantly less in tetraploid-evolved lines compared to the diploid-evolved lines. Taken together, this work supports a model of adaptation in which the tetraploid state is transient but its ability to rapidly transition ploidy states improves adaptative outcomes and may drive drug resistance in fungal pathogens.

evolutionary biology↗

bioRxiv2020

Host association induces genome changes in Candida albicans which alters its virulence

Candida albicans is an opportunistic fungal pathogen of humans that is typically diploid yet, has a highly labile genome that is 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 stress environments, like those encountered in the host. Genetic variation occurs via stress-induced mutagenesis or can be generated through its parasexual cycle, which includes mating between diploids or stress-induced mitotic defects to produce tetraploids and non-meiotic ploidy reduction. However, it remains largely unknown how genetic background contributes to C. albicans genome instability in vitro or in vivo. Here, we tested how genetic background, ploidy and host environment impact 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 strains. We also assessed whether host-induced genomic changes resulted in any consequences on growth rate and virulence phenotypes and found that many host derived isolates had significant changes compared to their parental strains. Interestingly, host derivatives from diploid C. albicans predominantly displayed increased virulence, whereas host derivatives from tetraploid C. albicans had mostly reduced virulence. Together, these results are important for understanding how host-induced genomic changes in C. albicans alter the relationship between the host and C. albicans.

microbiology↗

bioRxiv2019

The NAD+-dependent deacetylase Sir2 enables evolution of new traits by regulating distinct gene sets in two yeast species, Saccharomyces cerevisiae and Kluyveromyces lactis

Evolutionary adaptation increases the fitness of an organism in its environment. It can occur through rewiring of gene regulatory networks, such that an organism responds appropriately to environmental changes. We investigated whether sirtuin deacetylases, which repress transcription and require NAD+ for activity, could facilitate the evolution of potentially adaptive responses by serving as transcriptional rewiring points. If so, bringing genes under the control of sirtuins could enable organisms to mount appropriate responses to stresses that decrease NAD+ levels. To explore how the genomic targets of sirtuins shift over evolutionary time, we compared two yeast species, Saccharomyces cerevisiae and Kluyveromyces lactis that display differences in cellular metabolism and lifecycle timing in response to nutrient availability. We identified sirtuin-regulated genes through a combination of chromatin immunoprecipitation and RNA expression. In both species, regulated genes were associated with NAD+ homeostasis, mating, and sporulation, but the specific genes differed. In addition, regulated genes in K. lactis were associated with other processes, including utilization of non-glucose carbon sources, heavy metal efflux, DNA synthesis, and production of the siderophore pulcherrimin. Consistent with the species-restricted regulation of these genes, sirtuin deletion impacted relevant phenotypes in K. lactis but not S. cerevisiae. Finally, sirtuin-regulated gene sets were depleted for broadly-conserved genes, consistent with sirtuins regulating processes restricted to a few species. Taken together, these results are consistent with the notion that sirtuins serve as rewiring points that allow species to evolve distinct responses to low NAD+ stress.

evolutionary biology↗

bioRxiv2019

Ploidy determines the consequences of antifungal-induced mutagenesis in Candida albicans, a human fungal pathogen

Organismal ploidy state and environmental stress impact the mutational spectrum and the mutational rate. The human fungal pathogen Candida albicans, serves as a clinically relevant model for studying the interaction between eukaryotic ploidy and stress-induced mutagenesis. In this study, we compared the rates and types of genome perturbations in diploid and tetraploid C. albicans following exposure to two classes of antifungal drugs, azoles and echinocandins. We measured mutations at three different scales: point mutation, loss-of-heterozygosity (LOH), and genome size changes in cells treated with fluconazole and caspofungin. We find that caspofungin induced higher rates of mutation than fluconazole, likely an indirect result from the stress associated with cell wall perturbations rather than an inherent genotoxicity. Furthermore, we found disproportionately elevated rates of LOH and genome size changes in response to both antifungals in tetraploid C. albicans compared to diploid C. albicans, suggesting that the magnitude of stress-induced mutagenesis results from an interaction between ploidy state and the environment. These results have both clinical and evolutionary implications for how fungal pathogens generate mutations in response to antifungal drug stress, and may facilitate the emergence of antifungal resistance.

genetics↗

bioRxiv2019

Fungal virulence depends on interactions between pathogen ploidy and genetic background in healthy and immunocompromised hosts

Studying fungal virulence is often challenging and frequently depends on many contexts, including host immune status and pathogen genetic background. However, ploidy has often been overlooked when studying virulence in eukaryotic pathogens. Since fungal pathogens, including the human opportunistic pathogen Candida albicans, can display extensive ploidy variation, assessing how ploidy impacts virulence has important clinical relevance. Here, we assessed how C. albicans ploidy and genetic background impact virulence phenotypes in both healthy and immunocompromised nematode hosts. In addition to reducing overall host survival, Candida negatively impacted host reproduction, which allowed us to survey lethal and non-lethal virulence phenotypes. While we did not detect any global differences in virulence between diploid and tetraploid pathogens, there were significant interactions between ploidy and C. albicans genetic background, regardless of host immune function.

genetics↗

bioRxiv2018

A novel virulence phenotype rapidly assesses Candida fungal pathogenesis in healthy and immunocompromised Caenorhabditis elegans hosts

The yeast Candida albicans is an opportunistic pathogen of humans, meaning that despite commensal interactions with its host, it can transition to a harmful pathogen. While C. albicans is the predominant species isolated in the human mycobiome and implicated in fungal infection, infections due to non-albicans Candida species are rapidly rising. Studying the factors that contribute to virulence is often challenging and frequently depends on many contexts including host immune status and pathogen genetic background. Here, we utilize the nematode Caenorhabditis elegans as a perspicuous and efficient model host system to study fungal infections of Candida pathogens. We find that in addition to reducing lifetime host survival, exposure to C. albicans results in delayed reproduction, which significantly reduced lineage growth over multiple generations. Furthermore, we assessed fungal pathogen virulence in C. elegans hosts compromised for innate immune function and detected increased early mortality, reduced brood sizes and delayed reproduction relative to infected healthy hosts. Importantly, by assessing virulence in both healthy and immunocompromised host backgrounds we reveal the pathogen potential in non-albicans Candida species. Taken together, we present a novel lineage growth assay to measure reduction in host fitness associated with fungal infection and demonstrate significant interactions between pathogen and host immune function that contribute to virulence.

microbiology↗