Abstract
Bacteria harness diverse defense systems that protect against phage predation(1), many of which are encoded on horizontally transmitted mobile genetic elements (MGEs)(2). In turn, phages evolve counter-defenses(3), driving a dynamic arms race that remains underexplored in human disease contexts. For the diarrheal pathogen Vibrio cholerae, a higher burden of its lytic phage, ICP1, in patient stool correlates with reduced disease severity(4). However, direct molecular evidence of phage-driven selection of epidemic V. cholerae has not been demonstrated. Here, through clinical surveillance in cholera-endemic Bangladesh, we capture the acquisition of a parasitic anti-phage MGE, PLE11, that initiated a selective sweep coinciding with the largest cholera outbreak in recent records. PLE11 exhibited potent anti-phage activity against co-circulating ICP1, explaining its rapid and dominating emergence. We identify PLE11-encoded Rta as the novel defense responsible and provide evidence that Rta restricts phage tail assembly. Using experimental evolution, we predict phage counteradaptations against PLE11 and document the eventual emergence and selection of ICP1 that achieves a convergent evolutionary outcome. By probing how PLEs hijack phage structural proteins to drive their horizontal transmission while simultaneously restricting phage tail assembly, we discover that PLEs manipulate tail assembly to construct chimeric tails comprised of MGE and phage-encoded proteins. Collectively, our findings reveal the molecular basis of the natural selection of a globally significant pathogen and its virus in a clinically relevant context.