Resistance to echinocandins comes at a cost: the impact of FKS1 hotspot mutations on Candida albicans fitness and virulence

Abstract

The emergence of Candida strains carrying FKS1 hotspot mutations associated with resistance to echinocandins is cause for concern. However, to assess the potential of such strains to spread within the community and cause lethal infection, the impact of FKS1 mutations on Candida fitness must be determined. We present evidence that C. albicans fks1 mutations carry significant fitness and virulence costs, which are associated with the production of a thickened, chitin-rich cell wall, impaired filamentation and induction of a dampened inflammatory response. If these phenotypic changes remain stable, they can serve as a basis for rational design of strategies to control the spread of echinocandin resistance.

Figure 1. Phenotypic changes associated with FKS1 hotspot mutations in Candida albicans. C. albicans FKS1 hotspot mutations are associated with significant increases in cell-wall thickness attributed to increased cell-wall chitin content, impaired growth rate and filamentation capacity. Cell wall components are shown in brown (chitin), green (β-1,3-glucan), red (β-1,6-glucan) and purple (mannan). Production of thick chitinous cell walls likely results from upregulation of chitin synthesis as a result of activation of cell wall salvage pathways. FKS1 mutants exhibit attenuated fitness in vitro, and reduced lethality in immunocompetent BALB/c mice. Excised kidneys show attenuated fungal burdens and the absence of hyphal forms in tissue. It is hypothesized that in fks1 mutants cell-wall chitin blocks Dectin-1 signaling (Mora-Montes et al., Infect Immun 2011), thereby dampening the inflammatory response to β-glucans.