Cryptococcus neoformans constitutes an ideal model organism to unravel the contribution of cellular aging to the virulence of chronic infections

Abstract

Aging affects all organisms, from unicellular yeasts to multicellular humans. Studies in model organisms demonstrate that the pathways that mediate the two forms of aging, replicative and chronological, are highly conserved. Most studies are focused on the effect of aging on an individual cell rather than a whole population. Complex longevity regulation, however, makes aging a highly adaptive trait that is subject to natural selection. Recent studies have shed light on the potential relevance of aging in fungal pathogens, which undergo replicative aging when they expand in the host environment. Hence, pathogens causing chronic infections can constitute ideal model organisms in unraveling the contribution of selection to aging within a population and help elucidate the contribution of aging itself to the virulence of infections.

Figure 1. Bud scar stains can be used to quantitate age of a cell in S. cerevisiae, but are unreliable biomarkers in other fungi

(A) Calcofluor reliably stained for budscars of 0–2 generation and 8–10 generation old S. cerevisiae cells. (B) Bud scar straining with Calcofluor (data not shown), and wheat germ agglutinin lectin did not reliably distinguish 0–2 generation and 8–10 generation old C. neoformans cells.

Figure 2. Older C. neoformans and C. albicans cells had increased resistance to antifungals in time-kill assays

(A) Old (18 generations old) C. neoformans cells were more resistant to killing by therapeutic doses of amphotericin B and (B) fluconazole compared to young (0–2 generation old) cells. (C) Old (10 generation old) C. albicans cells were more resistant to killing by caspofungin compared to young (0–2 generation old) cells (*p < 0.02). Copyright © American Society for Microbiology, [Eukaryotic Cell, 6, 2009, 858-66, DOI: 10.1128/EC.00017-09]

Figure 3. Replicative lifespan (RLS) was different in cells of one strain and among different strains

The number of replications was determined by microdissection of individual C. neoformans cells from a lab passaged strain (H99), which had a heterogeneous RLS, but whose median RLS was reproducible. RLS of this strain was less variable than a low passaged strain (I58).