Host association induces genome changes inCandida albicanswhich alters its virulence

Abstract

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 stressinduced 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-ofheterozygosity 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. Introduction:Host-pathogen interactions are multi-faceted. As a fungal opportunistic pathogen of humans, Candida albicans has many different relationships with the host. Typically, C. albicans is commensal, residing in many niches in the human body, including the gastrointestinal and urogenital tracts, oral cavity, and the skin (1). However, C. albicans can be pathogenic and cause superficial mucosal infections and deadly bloodstream infections (2, 3). Much of the research regarding C. albicans has focused on its virulence factors, which include, filamentation, biofilm formation, secretory aspartyl proteinases (SAPs), and candidalysin production (4, 5). Host immune cells control C. albicans infection by recognizing fungal cells and producing antimicrobial peptides (AMPs) (6) and reactive oxygen species (ROS) which inhibit growth and cause DNA damage (7, 8) However, how host-induced genome alterations in C. albicans impact its relationship with the host is not well understood.Genomic alterations in C. albicans have important consequences in other clinical contexts, most importantly in acquiring resistance to the drugs used to treat fungal infections. Analysis of clinical isolates and laboratory studies show that chromosomal aneuploidy and homozygosis of hyper-active resistance alleles are associated with increased antifungal drug resistance (9-14). The ability to generate genetic variatio...