Salmonella and the oxidative burst : tales of a complicated relationship.

Salmonella is one of the most abundant bacterial pathogens infecting humans in developed and developing countries. It is the causative agent of disease and mortality resulting in billions of dollars in associated medical costs and lost productivity every year. In the laboratory, findings regarding the physiology of Salmonella infections are often used to model a wide range of bacterial infections impacting fields far beyond the scope of Salmonella pathogenesis alone. For these reasons, significant resources have been dedicated to gaining a better understanding of mechanisms underlying Salmonella infection and the interaction between the pathogen and the immune system. In this thesis, Salmonella is used to study the interaction between bacterial pathogens and the host’s oxidative and nitrosative burst. Recently, new findings have challenged the conventional perspective of reactive oxygen and nitrogen species as merely antimicrobial agents by revealing redox-sensitive virulence mechanisms that benefit Salmonella infection. These new findings, together with processes that drive Salmonella infection, are highlighted in Chapter 1. To better address questions concerning redox stress inside bacteria we used redox-sensitive GFP which enabled real-time analysis of the intra-bacterial redox environment. In Chapter 2 this redox-biosensor combined with high-throughput microscopy, was used to evaluate oxidative/nitrosative stress evasion strategies inside macrophages. In Chapter 3, the same method was used to explore the bacterial outer membrane permeability to hydrogen peroxide. Real-time measurements of the intra-bacterial redox potential revealed novel regulatory mechanisms that alter outer membrane permeability based on the presence or absence of reactive oxygen and nitrogen species. Chapter 4 describes the identification and characterization of a redox-sensitive regulatory modification in Salmonella effector SteB. This modification was found to be crucial for regulation of tubulin-mediated transport of the Salmonella containing vacuole. Cumulatively these studies describe strategies for oxidative/nitrosative stress evasion while also highlighting several mechanisms by which reactive oxygen and nitrogen species aid Salmonella during infection. In Chapter 5, these findings have been integrated in order to gain a more comprehensive understanding of the complicated relationship between Salmonella and oxidative/nitrosative stress which has the potential to lead to the development of novel antimicrobial therapies.

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