Infectious diseases cause one in four deaths worldwide. Emerging infectious diseases continue to threaten public health on a global scale as novel zoonotic pathogens cause human disease, strains of existing microbes develop antimicrobial resistance, and the spread of pathogens alters as a result of human activities. Novel strategies are required to contain these emerging pathogens and reduce their impact on society. In order to optimize the development of such countermeasures, the interactions between host and pathogen and their impact on the efficacy of vaccination and antibiotic therapy must be elucidated. Here we describe the challenges emerging pathogens present to society using several recent outbreaks as examples of how human activity has collided with microbial evolution to create worldwide health crises and support the urgent need for novel therapeutics and strategies to counter these pathogens.

This is followed by the rational design of a live-attenuated vaccine for the zoonotic pathogen Yersinia pseudotuberculosis that elicits cross-protective immunity against several clinically relevant serotypes. A vaccine that elicits heterologous protection against a variety of pathogenic serotypes is ideal for mitigating illness in humans and animals, especially for use in the livestock industry. The final part of this dissertation discusses the identification of transient antibiotic resistance evident in Salmonella only upon infection of a host or in host-mimicking conditions. This phenotype characterized by inducible high-level antibiotic resistance, termed transient in vivo antibiotic resistance (TIVAR), is rapidly induced and reversible and only occurs within certain host compartments (tissue-specific). TIVAR results in antibiotic treatment failure and the enhanced selection of stable resistance.

Collectively, this work supports the development of novel strategies to counter emerging bacterial pathogens by evaluating the interactions that underlie vaccine-elicited cross-protective immunity and the induction of transient antibiotic resistance during infection.