Replicative Aging in Pathogenic Fungi

Abstract

Candida albicans, Candida auris, Candida glabrata, and Cryptococcus neoformans are pathogenic yeasts which can cause systemic infections in immune-compromised as well as immune-competent individuals. These yeasts undergo replicative aging analogous to a process first described in the nonpathogenic yeast Saccharomyces cerevisiae. The hallmark of replicative aging is the asymmetric cell division of mother yeast cells that leads to the production of a phenotypically distinct daughter cell. Several techniques to study aging that have been pioneered in S. cerevisiae have been adapted to study aging in other pathogenic yeasts. The studies indicate that aging is relevant for virulence in pathogenic fungi. As the mother yeast cell progressively ages, every ensuing asymmetric cell division leads to striking phenotypic changes, which results in increased antifungal and antiphagocytic resistance. This review summarizes the various techniques that are used to study replicative aging in pathogenic fungi along with their limitations. Additionally, the review summarizes some key phenotypic variations that have been identified and are associated with changes in virulence or resistance and thus promote persistence of older cells.

Candida glabrata: Pathogenicity and Resistance Mechanisms for Adaptation and Survival

“…The total number of buds that a mother cell produces before the division ceases and dies is the designated replicative life span (RLS). Each cycle of bud formation by a mother cell represents one generation [ 75 ]. Several studies showed that replicative ageing in many fungal pathogens leads to significant changes that affect the fungal resistance to phagocytic clearance and antifungal therapy [ 75 ].…”

“…Each cycle of bud formation by a mother cell represents one generation [ 75 ]. Several studies showed that replicative ageing in many fungal pathogens leads to significant changes that affect the fungal resistance to phagocytic clearance and antifungal therapy [ 75 ]. The phenotypic changes in the daughter cells due to ageing are not genetically inherited.…”

“…The phenotypic changes in the daughter cells due to ageing are not genetically inherited. The old cells only emerge because of neutrophil pressure in the environment that favour the killing of young fungal cells and the promotion of the persistence of old cells [ 75 ]. Thus, for the pathogen, this form of adaptation is advantageous, as it avoids the risk of random permanent mutations and instead assures that all adaptive changes are easily reversed in the daughter cells that are borne from asymmetric budding.…”

What Do We Know about Candida auris? State of the Art, Knowledge Gaps, and Future Directions

“…Furthermore, beyond molecular mechanisms of antifungal resistance in C. auris , phenotypic modifications and biofilm formation also influence the degree of drug resistance [ 61 , 108 , 110 ]. As previously stated, replicative aging resulting in asymmetric cell division and phenotypically distinct daughter cells has been associated with increased virulence, but also drug resistance [ 111 , 133 ]. Senescent C. auris cells showed a higher tolerance to fluconazole, micafungin, flucytosine, and amphotericin B. Bhattacharya et al [ 111 ] demonstrated that fluconazole resistance in these cells was due to gene duplication in CDR1 and ERG11.…”

Replicative Aging Remodels Cell Wall and is Associated with Increased Intracellular Trafficking in Human Pathogenic Yeasts

“…Aging is the consequence of cell division and a conserved natural process among eukaryotic cells. Replicative aging is the result of asymmetric cell divisions, and is an important contributor to pathogenesis (20). During replicative aging, the fungal cell wall becomes thicker, which is associated with increased resistance to antifungals and phagocytic uptake (21, 22).…”