Selection of Candida albicans trisomy during oropharyngeal infection results in a commensal-like phenotype.

Anja Forche,Robert Thomas,Anna Selmecki,Alison Guyer,Annette Beach,Norma V Solis,Norman Pavelka,Gareth A Cromie,Aimeé M Dudley,Marc Swidergall,Scott G Filler,Emily Lowell,Judith Berman,Giang T Le

doi:10.1371/journal.pgen.1008137

Abstract

When the fungus Candida albicans proliferates in the oropharyngeal cavity during experimental oropharyngeal candidiasis (OPC), it undergoes large-scale genome changes at a much higher frequency than when it grows in vitro. Previously, we identified a specific whole chromosome amplification, trisomy of Chr6 (Chr6x3), that was highly overrepresented among strains recovered from the tongues of mice with OPC. To determine the functional significance of this trisomy, we assessed the virulence of two Chr6 trisomic strains and a Chr5 trisomic strain in the mouse model of OPC. We also analyzed the expression of virulence-associated traits in vitro. All three trisomic strains exhibited characteristics of a commensal during OPC in mice. They achieved the same oral fungal burden as the diploid progenitor strain but caused significantly less weight loss and elicited a significantly lower inflammatory host response. In vitro, all three trisomic strains had reduced capacity to adhere to and invade oral epithelial cells and increased susceptibility to neutrophil killing. Whole genome sequencing of pre- and post-infection isolates found that the trisomies were usually maintained. Most post-infection isolates also contained de novo point mutations, but these were not conserved. While in vitro growth assays did not reveal phenotypes specific to de novo point mutations, they did reveal novel phenotypes specific to each lineage. These data reveal that during OPC, clones that are trisomic for Chr5 or Chr6 are selected and they facilitate a commensal-like phenotype.

Highlights

Our recent study of rapid C. albicans genome diversification during oropharyngeal candidiasis (OPC) identified a specific whole Chr amplification, trisomy of Chr 6 (Chr6x3), that was highly overrepresented among strains recovered from the tongues of mice after one round of infection
Our results reveal that Chr5x3 or Chr6x3 clones have a commensal-like phenotype that was apparently selected during OPC infection
The frequency of Chr6x3 increased over the course of infection (Fig 1A) with the allele combination ABB occurring 2-fold more frequently than the AAB combination (Fig 1B), suggesting that clones with trisomy of Chr6 have a general fitness advantage during OPC and that an extra copy of allele B may be more beneficial than an extra copy of allele A in this host niche

Summary

Introduction

Multiple outcomes including colonization, commensalism, latency and disease are possible [1,2,3]. The immune status of the host is a key factor that determines the outcome of fungus-host interactions, especially for opportunistic fungi [4,5,6]. It has been appreciated that the genotype of the fungus determines the outcome of this interaction. In C. albicans, intra-species diversity among clinical strains results in differential modulation of fungus-host interactions [7]. Intra-species diversity of Cryptococcus neoformans is associated with different clinical outcomes in patients with cryptococcal meningitis [8]

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Discussion

Conclusion