Molecular mechanisms underlying the host range of bacteriophages infecting Shiga toxin-producing Escherichia coli strains

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Bacteriophages (phages) are the most abundant entities across all habitats, and a major reservoir of genetic diversity, affecting microbial structure and ecosystem dynamics. The scope of hostviral interactions is poorly understood, although hypothetically all cellular organisms are prey to viral attack. Shiga-toxigenic Escherichia coli (STEC) are a diverse group of zoonotic pathogens, causing foodborne disease worldwide. New pathogenic serogroups keep emerging, but cattle and their environment continue to be the primary reservoir for STEC. Effective pre-harvest interventions are critical to minimize STEC contamination in the food supply chain. Endogenous phages are ubiquitous in cattle and their environment, regulating diversity of STEC via unknown mechanisms. Gaining mechanistic insights regarding how phages adapt to the cattle environment and prey on a variety of STEC is imperative to understand STEC ecology, and enhance phage biocontrol outcomes to mitigate STEC shedding in cattle. Molecular mechanisms that support phage-bacteria interactions are encoded in phage and host genomes. The long-term objectives of my research program are to understand how environmental phage genomes change and co-evolve with bacteria and how this shapes bacterial community structures and populations. Using a combination of approaches, including genomics, bioinformatics, genome-fitness assays and synthetic biology, my research program examines gene variety and specialization of phages and associated linkage to STEC recognition and infectivity. Availability of >70 STEC phages across 3 families enable us to address various key questions in their interactome with their host. We will determine how phage tail genes are diversified and patterned in response to divergent STEC surface structure. We will also genetically identify STEC surface structures involved in phage binding. For broad host-range phages, we will explore whether they can recognize and attach to conserved host surface structures to initiate infection. Finally, we will use genome editing to modify phage tail genes in an attempt to alter their host specificity. The proposed program is the first to systematically investigate initial interplays between various genotypes of phages and diverse serogroups of STEC, generating new knowledge on molecular mechanisms underlying host recognition and infection of STEC phages. Addressing these research objectives should greatly improve understanding of how phage genomes adapt in response to natural environments and how these changes promote adaptation and specialization in new environments. In addition, the proposed program aims to address Canada's urgent food safety challenges of pathogenic E. coli by elucidating fundamental knowledge at the primary-production level. This program will generate well trained HQP specialized in phage biology and proficient in cutting-edge technologies and other essential skills, enabling them to excel in academia, industry and elsewhere.