Salmonella persistence in diverse intracellular and physiological contexts

Abstract

Antibiotic-recalcitrant infections, defined as the prolonged carriage of pathogenic bacteria even in the presence of antibiotics, are often caused by bacteria that are genetically susceptible to the drug. These recalcitrant bacteria fail to proliferate in the presence of antibiotics but remain viable such that they may recolonize their niche following antibiotic withdrawal. In the context of Salmonella infections, these antibiotic-recalcitrant infections are commonly caused by persisters, a non-growing, metabolically active bacterial subpopulation. Although much progress has been made in the study of persistent Salmonella, it remains unclear whether persister cells are the true source of relapsing disease, and whether other relevant intracellular persistence niches exist in addition to macrophages. In Chapter 1, I will provide a comprehensive overview of what is currently understood about antibiotic recalcitrance during Salmonella infection, including areas of active investigation. In Chapter 2, I will specifically explore the role of persister cells in infection relapse using the novel application of two methods to identify the source and nature of infection relapse. Then, in Chapter 3, I will discuss how we identified dendritic cells as an underappreciated niche for Salmonella persistence, and how the repeating O antigen moiety of lipopolysaccharide promotes persistence in both dendritic cells and macrophages by an as-yet unknown mechanism. Finally, Chapter 4 will summarize our broadened understanding of persistence and infection relapse and provide suggestions for future avenues of exploration. Through this dissertation and the work that will stem from it, we hope to gain a greater understanding of the mechanisms of infection relapse, allowing for more informed treatment decisions and a reduced incidence of recurrent disease.