Abstract
The evolution of pathogens in response to selective pressures present during chronic infections can influence their persistence and virulence and the outcomes of antimicrobial therapy. Because subpopulations within an infection can be spatially separated and the host environment can fluctuate, an appreciation of the pathways under selection may be most easily revealed through the analysis of numerous isolates from single infections. Here, we continued our analysis of a set of clonally derived Clavispora (Candida) lusitaniae isolates from a single chronic lung infection with a striking enrichment in the number of alleles of MRR1 Genetic and genomic analyses found evidence for repeated acquisition of gain-of-function mutations that conferred constitutive Mrr1 activity. In the same population, there were multiple alleles with both gain-of-function mutations and secondary suppressor mutations that either attenuated or abolished the constitutive activity, suggesting the presence of counteracting selective pressures. Our studies demonstrated trade-offs between high Mrr1 activity, which confers resistance to the antifungal fluconazole, host factors, and bacterial products through its regulation of MDR1, and resistance to hydrogen peroxide, a reactive oxygen species produced in the neutrophilic environment associated with this infection. This inverse correlation between high Mrr1 activity and hydrogen peroxide resistance was observed in multiple Candida species and in serially collected populations from this individual over 3 years. These data lead us to propose that dynamic or variable selective pressures can be reflected in population genomics and that these dynamics can complicate the drug resistance profile of the population.IMPORTANCE Understanding microbial evolution within patients is critical for managing chronic infections and understanding host-pathogen interactions. Here, our analysis of multiple MRR1 alleles in isolates from a single Clavispora (Candida) lusitaniae infection revealed the selection for both high and low Mrr1 activity. Our studies reveal trade-offs between high Mrr1 activity, which confers resistance to the commonly used antifungal fluconazole, host antimicrobial peptides, and bacterial products, and resistance to hydrogen peroxide. This work suggests that spatial or temporal differences within chronic infections can support a large amount of dynamic and parallel evolution and that Mrr1 activity is under both positive and negative selective pressure to balance different traits that are important for microbial survival.
Highlights
Understanding the positive and negative selective pressures that shape drug resistance profiles in microbial populations is critical for combating the development of antimicrobial resistance, an ever-increasing problem in clinical settings
In Demers et al [10], we described a set of twenty recently-diverged Clavispora (Candida) lusitaniae isolates obtained from the lung infection of a single individual with cystic fibrosis (CF)
Each of the twenty closely-related C. lusitaniae isolates from a single individual contained at least one nonsynonymous single nucleotide polymorphism (SNP) or single nucleotide insertion or deletion in MRR1 relative to the deduced MRR1 sequence of their most recent common ancestor (MRR1ancestral) (Fig. 1A) [10]
Summary
Understanding the positive and negative selective pressures that shape drug resistance profiles in microbial populations is critical for combating the development of antimicrobial resistance, an ever-increasing problem in clinical settings. Increased drug resistance in bacteria and fungi has been associated with clinically- and agriculturally-used antimicrobial agents (reviewed in [1,2,3]), and drug resistance elements may be selected for based on their ability to protect against factors produced by other microbes or plant, animal, and insect hosts [4, 5]. Based on the analysis of bacterial isolates of Burkholderia dolosa or Pseudomonas aeruginosa from single patients and across cohorts of patients, it is clear that in vivo factors can lead to the repeated selection for subpopulations with the same genes or pathways mutated [6,7,8]. Suppressor mutations within P. aeruginosa algU frequently arise in strains with high AlgU signaling caused by mutations in the gene encoding the AlgU repressor MucA [9].
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