Short-term evolution strategies for host adaptation and drug escape in human fungal pathogens

Abstract

Research on human fungal pathogens has historically taken a backseat to other infectious diseases, perhaps due to a common misperception that fungi largely cause superficial infections [1]. In reality, fungi can be life-threatening to those who become immunocompromised during medical procedures or through conditions such as HIV and diabetes. Invasive fungal infections are estimated to kill over 1 million people every year, with mortality rates reaching 50% [2]. Significant challenges to the treatment of fungal infections include the limited availability of antifungals and the innate ability of fungi to rapidly evolve and adapt to fluctuating conditions. This adaptive ability is partially driven by extensive genomic plasticity, with many species acquiring diverse ploidy states, chromosomal rearrangements, and point mutations during host colonization [3-8]. Genetic plasticity enables rapid increases in virulence and antifungal drug resistance, which often translate to poor disease outcomes. Short-term evolution (microevolution) strategies in fungal pathogens are therefore essential for environmental adaptation in the mammalian host, and their study can inform adaptive mechanisms in other eukaryotes. Ploidy shifts enable rapid fitness jumps under stressful conditions Many clinically relevant fungi display dynamic changes in ploidy, including both karyotypic variations (number of sets of chromosomes) as well as aneuploidy (imbalance in chromosome copy number). Some fungal pathogens exist as stable haploid, diploid, or polyploid cells, but ploidy can change upon shifting conditions. Alterations in baseline ploidy have been described for some of the most prevalent genera (Candida, Cryptococcus, and Aspergillus) and are often selected for in the host or during antifungal treatment. Extra chromosomes are common in isolates from human infections [5, 6, 8, 9] and after passage through mammalian hosts during experimental microevolution [10-12]. Under nutrient starvation, Candida albicans isolates can favor either near-haploid or near-diploid states, indicating that karyotypic reduction can provide an efficient adaptive route in some conditions [13]. Aneuploidy is also common in C. albicans and in Cryptococcus neoformans lineages and has been linked to increased virulence and drug resistance [14] [15]. Chromosomal duplication can mediate adaptation through gene dosage, as transcript levels are often proportional to gene copy number [16]. This can be seen in both C. albicans and Cryptococcus species, for which antifungal treatment selects for increased copies of chromosomes or chromosomal segments containing drug targets and/or efflux pumps. Thus, clinical isolates of Cryptococcus lineages VNI and VGI that persisted during fluconazole therapy were frequently disomic for chromosome 1 [5]. Analogous in vitro fluconazole treatment of Cryptococcus lineages VNI and VNIV selected for disomy of

Loss of heterozygosity results in rapid but variable genome homogenization across yeast genetic backgrounds

“…LOH events have been identified as involved in fitness, adaptation, and pathogenesis in many fungi (20)(21)(22). In addition, LOH is also a common genetic event in cancer development (15).…”

Clonal evolution in serially passagedCryptococcus neoformansxdeneoformanshybrids reveals a heterogenous landscape of genomic change

“…Aneuploidy leading to CNV is a rapid means of generating adaptive genetic variation in pathogenic fungi (Bennett et al . 2014; Beekman and Ene 2020). We tested for the presence of both whole chromosomal and partial chromosomal aneuploidy by using density of reads mapped to the genome.…”

“…Aneuploidy leading to chromosomal copy number variation is a rapid means with which pathogenic fungi generate adaptive genetic variation (Bennett et al 2014;Beekman and Ene 2020). We tested for the presence of both whole chromosomal and partial chromosomal aneuploidy by using the density of reads mapped to a hybrid version of the genome, which we found to give a clearer picture of depth of coverage than solely using one species reference genome.…”

Genetic Susceptibility to Fungal Infections and Links to Human Ancestry

“…Structural genome variations like aneuploidy and copy number variations (CNVs) also provide important clues to fungal virulence ( Tsai and Nelliat, 2019 ). During fungal microevolution, many of these events like insertion/deletion of genes, loss of heterozygosity (LOH), and genome plasticity help fungus to adapt against antifungal drugs and harsh host environment ( Beekman and Ene, 2020 ). Thus, as part of preventive medicine, a better understanding of host genetics behind fungal infection will help us to study infectious diseases through modern genomic approaches and offer personalized therapy against invasive fungal diseases.…”