Evolution of Staphylococcus aureus phenotypes 公开
Su, Michelle (Summer 2020)
Abstract
Staphylococcus aureus poses a significant threat partly due to its incredible ability to adapt and evolve. Its evolution can be defined by parallel evolution, epistasis, and/or trade-offs between phenotypes. Understanding the selective pressures and constraints that influence the fitness landscape and mutational space S. aureus has access to will be a step towards better infection management and treatment. Antimicrobial resistance phenotype prediction is largely accurate due to well-characterized resistance determinants. Errors have been mainly attributed to the variability of culture-based antimicrobial susceptibility tests, but undefined epistasis can also dramatically affect the phenotypic manifestation of a resistance gene. Delta-toxin production in S. aureus, which is linked to atopic dermatitis, was found to be highly associated with clonal complex, indicating epistasis is the primary constraint is its evolution. Additionally, a genome-wide association study identified carA, carbamoyl-phosphate synthase small chain, as necessary for the expression of delta-toxin, confirming the link between virulence and metabolic status. Vancomycin resistance in S. aureus was confirmed to be driven largely by parallel evolution using experimental evolution in three backgrounds (CC1, CC5, CC8), but epistasis nonetheless affected the mutational patterns observed in these strains. In addition, differential fitness costs were seen in different genetic backgrounds during the progression from lower levels of resistance to higher levels of resistance. Virulence evolution of S. aureus in Caenorhabditis elegans was determined to exert selective pressure on virulence regulators and metabolic loci. In addition, there were trade-offs found between virulence and antibiotic exposure, which could be potentiated by host exposure. These studies together highlight the complex interplay between genetic background and outside selective forces and furthers our understanding the evolutionary dynamics of S. aureus phenotypes.
Table of Contents
Table of Contents
Chapter I. Introduction ………………………………………………………...…...……………. 1
Chapter II. Genome-Based Prediction of Bacterial Antibiotic Resistance …………...…………… 12
Chapter III. Genomic analysis of variability in Delta-toxin levels between Staphylococcus aureus strains …………………………………………………………………………………………… 38
Chapter IV. Effect of genetic background on the direction of evolution of Vancomycin-Intermediate Staphylococcus aureus (VISA) …………………………………………………………………… 88
Chapter V. Trade-offs between virulence and antibiotic resistance in Staphylococcus aureus during selection in the model host, Caenorhabditis elegans ……………………………………………... 122
Chapter VI. Discussion …………………………………………………………...…………… 143
References. ……………………………………………………………………………………. 150
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