β-glucan Exposure on the Fungal Cell Wall Tightly Correlates with Competitive Fitness of Candida Species in the Mouse Gastrointestinal Tract

Abstract

Candida albicans is responsible for ~400,000 systemic fungal infections annually, with an associated mortality rate of 46–75%. The human gastrointestinal (GI) tract represents the largest natural reservoir of Candida species and is a major source of systemic fungal infections. However, the factors that control GI colonization by Candida species are not completely understood. We hypothesized that the fungal cell wall would play an important role in determining the competitive fitness of Candida species in the mammalian GI tract. To test this hypothesis, we generated a systematic collection of isogenic C. albicans cell wall mutants and measured their fitness in the mouse GI tract via quantitative competition assays. Whereas a large variation in competitive fitness was found among mutants, no correlation was observed between GI fitness and total levels of individual cell wall components. Similar results were obtained in a set of distantly-related Candida species, suggesting that total amounts of individual cell wall components do not determine the ability of fungi to colonize the GI tract. We then subjected this collection of Candida strains and species to an extensive quantitative phenotypic profiling in search for features that might be responsible for their differences in GI fitness, but found no association with the ability to grow in GI-mimicking and stressful environments or with in vitro and in vivo virulence. The most significant association with GI fitness was found to be the strength of signaling through the Dectin-1 receptor. Using a quantitative assay to measure the amount of exposed β-glucan on the surface of fungal cells, we found this parameter, unlike total β-glucan levels, to be strongly predictive of competitive fitness in the mouse GI tract. These data suggest that fungal cell wall architecture, more so than its crude composition, critically determines the ability of fungi to colonize the mammalian GI tract. In particular, recognition of exposed β-glucan by Dectin-1 receptor appears to severely limit Candida GI fitness and hence represents a promising target to reduce fungal colonization in patients at risks of systemic candidiasis.

Selection of Candida albicans Trisomy during Oropharyngeal Infection Results in a Commensal-Like Phenotype

“…Accordingly, the amount of exposed β-glucan on the surface of fungal 281 cells was strongly predictive of competitive fitness in the mouse GI tract (Ene et al 2018). Furthermore, 282 fungal cell wall architecture, rather than cell wall composition, determines the ability of fungi to colonize 283 the GI tract (Sem et al 2016). Finally, a recent study on functional divergence of filamentous growth 284 regulation in C. albicans found that Flo8 overexpression was sufficient to restore filamentation in a 285 mfg1/mfg1 mutant (Polvi et al 2019).…”

Fungal symbionts produce prostaglandin E2to promote their intestinal colonization

“…The abundance of each strain relative to that of SC5314-dTomato was determined at regular intervals by plating the cultures on yeast peptone dextrose (YPD) agar followed by scoring of fluorescent and non-fluorescent colonies. The fitness of each strain can in turn be quantified by deriving a fitness coefficient from the rate of change of the relative abundance of each strain [13]. Even after 80 h (equivalent to ~44 and 63 generations for growth in YNB and YPD, respectively) of serial subculturing, we detected no differences in competitive fitness between the ole2/ole2 and WT strains in both a nutrient-rich YPD broth and a nutrient-poor yeast nitrogen base (YNB) media (Fig 2).…”

“…In an earlier report, we had demonstrated that the extent of surface β-glucan exposure by fungal cells and their consequent triggering of dectin-1 signaling correlate strongly with the in vivo intestinal fitness of Candida species [13]. We thus sought to determine if fungal PGE 2 modulates fungal fitness in the murine gut by tuning β-glucan exposure on fungal cell wall surfaces.…”

“…Accordingly, some of the aforementioned genetic programs in C. albicans might also promote intestinal symbiosis by calibrating the host immune response towards the fungus or vice versa . For instance, cell wall remodeling can mask the exposure of β-glucan, an essential component of fungal cell walls, to host immunological sensing via dectin-1 [16, 17], and recognition of surface β-glucan by dectin-1 is strongly correlated with the competitive fitness of Candida species in the murine intestine [13]. In addition, C. albicans upregulates the key morphogenetic regulator, EFG1 , upon colonizing the gut, and EFG1 is required for C. albicans to overcome host immunological pressures to persist in the GI tract long-term [18].…”

Ploidy Variation in Fungi: Polyploidy, Aneuploidy, and Genome Evolution

“…This suggests that some of these aneuploid states may be adaptive. Interestingly, the dramatic changes in ploidy may be specific to pathogenic host niches: passage of C. albicans using a murine commensal model found no ploidy or chromosome copy number changes by flow cytometry and WGS (142), supporting that host microenvironment impacts genome architecture.…”