UC San Diego

For billions of years, bacteria and their viruses (termed phages) have engaged in never-ending cycles of coevolution, as bacteria evolve resistance and phages counter resistance. This process of reciprocal adaptation has fundamentally shaped the biology of bacteria and phages, as well as structured the microbial ecosystems of our planet’s oceans, soils, and organisms. In recent years, the evolution and spread of antibiotic resistant bacterial pathogens have renewed interest in phages as an alternative way to treat bacterial infections. Yet, only by understanding how phages interact and coevolve with their hosts can we devise effective treatment strategies that avoid recreating the past mistakes made with antibiotic drugs. In this dissertation, I take an applied perspective to study and better understand bacteria-phage coevolution. In the first chapter, I demonstrate that the therapeutic potential of phages can be enhanced by pre-adapting them to target pathogens via a process called coevolutionary training. In the second chapter, I evaluate how bacteria respond to trained phages compared to favored approaches in phage therapy, such as phage cocktails. In the third chapter, I study how bacteria-phage coevolution generates diversity and creates complex ecological networks. And in the fourth chapter, I use an in vivo mouse model to show that phages administered to the gut can modify the gut microbiome and affect host mouse body weight phenotypes. Altogether, this work reveals the importance of coevolution as a fundamental process that shapes the diversity of life and as a useful tool for applications such as phage therapy.