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Bacteria-phage conflicts: crucibles for molecular innovation and evolution

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Our lab is currently interested in host-pathogen conflicts and coevolution. We study this problem in the context of bacteria and the viruses, called bacteriophages, that infect them. There are an estimated 10^30 bacteria and 10^31 phages on the planet that have been locked in a fierce coevolutionary battle for billions of years. Phages can infect bacteria, commandeering host resources to rapidly replicate themselves before bursting out of the cell to infect yet other cells. To combat this lethal threat, bacteria have evolved sophisticated immunity mechanisms to defend themselves against phages, which, in turn, has driven the evolution of equally sophisticated counter-defense mechanisms in phage. These coevolutionary battles are the crucibles of molecular innovation, leading to immunity mechanisms such as restriction-modification and CRISPR-Cas systems. In recent years it has become clear that many more anti-phage defense systems and phage-encoded counter-defense systems remain to be discovered and characterized. We are engaged in both discovery efforts to systematically identify anti-phage defense systems and deep mechanistic studies of specific systems. We use a combination of genetics, biochemistry, microscopy, computational analyses, and genome-scale approaches. Our work is rooted in a desire to develop a deep, fundamental understanding of how bacteria function and evolve, but also has implications for, and applications in, phage therapy and the development of next-generation, precision molecular tools.

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We also have a long-standing interest in the specificity and evolution of protein-protein interactions. We previously approached this problem in the context of two-component signaling proteins, but now study toxin-antitoxin systems and protein-protein interfaces relevant to bacterial-phage interactions. These studies include experimental investigations of protein evolution both in vitro and in vivo, ancestral protein reconstructions, directed evolution studies, and often the use of comprehensive and combinatorial complete mutant libraries coupled to deep sequencing readouts.

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To learn more about specific projects, click here.