Genomic epidemiology of bacterial pathogen transmission, persistence, and resistance Restricted; Files Only
Talbot, Brooke (Fall 2024)
Abstract
This dissertation broadens the application of evolutionary concepts within applied epidemiology to enhance and go beyond traditional case detection and diagnostics. It aims to identify the strengths and limitations of genomic approaches when paired with clinical and epidemiological data. I use methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections as a model for exploring within host and between host pathogen evolution and to test the capacity of single species comparative genomics to detect epidemiological linkages. I also expand on the relationship between genetic distance and spread using a metagenomic analysis of antimicrobial resistance (AMR) genes in two different colocalized hosts, humans and gray mouse lemurs. First, I critically evaluate the use of single nucleotide polymorphism (SNP) thresholds in hospital-associated spread of S. aureus and Pseudomonas aeruginosa. I argue that a one-size-fits-all approach for SNP difference is insufficient due to evolutionary and ecological differences influencing genomic variability, even within the same epidemiological setting. I next investigate whether patients experiencing MRSA bacteremia exist in genomic clusters with epidemiological links based on SNP distance. I identified that genomic alignment strategy, and the genetic background of strains affect the detection of SNP differences and that bacteremia patients in clusters have common healthcare exposures long before illness onset. I then examine risk factors for MRSA bacteremia recurrence and whether recurrent strains share convergent adaptive traits. I show that in our study set most recurrent infections are relapses from previous strains. These relapse lineages exhibit signatures of positive selection, particularly in genes associated with antibiotic resistance and virulence. Finally, I characterized the AMR resistomes between human and lemur gut microbiomes using metagenomics. The study identified distinct bacterial species profiles but shared antimicrobial resistance genes between hosts and suggests that AMR gene spread is diffuse in this system. This research demonstrates how genomics offers more precise and predictive public health interventions by refining our understanding of pathogen transmission and recurrence and emphasizing that evolutionary dynamics beyond neutrally evolving genes demark epidemiological linkages.
Table of Contents
able of Contents
CHAPTER 1: INTRODUCTION 1
OVERVIEW OF PATHOGEN GENOMIC EPIDEMIOLOGY 1
ANTIBIOTIC RESISTANCE AS A PUBLIC HEALTH TARGET 3
STAPHYLOCOCCUS AUREUS: A PATHOGENESIS MODEL 7
SUMMARY OF CHAPTERS 11
CHAPTER 2: WHAT’S IN A SNP?: DEDUCING TRANSMISSION EVENTS OF BACTERIAL INFECTIONS USING GENETIC THRESHOLDS OF RELATEDNESS 15
ABSTRACT 15
INTRODUCTION 16
ECOLOGY, EPIDEMIOLOGY, EVOLUTION, OH MY! 17
JUSTIFICATIONS FOR SNP THRESHOLDS BETWEEN BACTERIAL INFECTIONS 19
USE CASES: INTERPRETING THRESHOLDS ACROSS HEALTHCARE-ASSOCIATED PATHOGENS 21
RANDOM MUTATIONS AND SUBSTITUTION RATE 27
HOMOLOGOUS RECOMBINATION 29
ADAPTATION TO THE HOST AND ENVIRONMENT 31
INTRAHOST DEMOGRAPHY OF BACTERIAL INFECTIONS 34
INTERHOST AND ENVIRONMENTAL RICHNESS 35
CONCLUSION 38
SUPPLEMENTARY TABLES 40
CHAPTER 3: UNSUSPECTED CLONAL SPREAD OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS CAUSING BLOODSTREAM INFECTIONS IN HOSPITALIZED ADULTS DETECTED USING WHOLE GENOME SEQUENCING 45
ABSTRACT 45
INTRODUCTION 46
METHODS 48
RESULTS 52
DISCUSSION 63
ADDITIONAL INFORMATION AND DECLARATIONS 66
SUPPLEMENTARY INFORMATION 67
CHAPTER 4: GENOMIC INVESTIGATION OF MRSA BACTEREMIA RELAPSE REVEALS DIVERSE GENOMIC PROFILES BUT CONVERGENCE IN BACTEREMIA-ASSOCIATED GENES 73
ABSTRACT 73
INTRODUCTION 74
METHODS 77
RESULTS 83
DISCUSSION 99
SUPPLEMENTAL MATERIAL 105
CHAPTER 5: METAGENOME-WIDE CHARACTERIZATION OF SHARED ANTIMICROBIAL RESISTANCE GENES IN SYMPATRIC PEOPLE AND LEMURS IN RURAL MADAGASCAR 123
ABSTRACT 123
INTRODUCTION 124
MATERIALS & METHODS 127
RESULTS 133
DISCUSSION 145
ADDITIONAL INFORMATION AND DECLARATIONS 150
SUPPLEMENTARY MATERIAL 152
CHAPTER 6: CONCLUSION 156
SUMMARY AND DISCUSSION 156
FUTURE DIRECTIONS 160
REFERENCES 163
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File download under embargo until 09 January 2026 | 2024-11-04 18:58:06 -0500 | File download under embargo until 09 January 2026 |
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