The circulating phageome reflects bacterial infections

Abstract Bacteriophage, viruses that infect bacteria, are abundant in the human body but the relationship between the phageome and bacterial population dynamics is unclear. Because bacteriophage are often highly specific to bacterial host strains and species, we asked whether bacteriophage present in cell-free DNA (cfDNA) reflect bacterial infections in sepsis and other infections. To address this, we generate a computational pipeline for identifying bacteriophage sequences in cfDNA. In three large, independent cohorts of infected patients and asymptomatic controls, we demonstrate that all individuals have a circulating phageome. Moreover, infection associates with overrepresentation of pathogen-specific phage, allowing for identification of bacterial pathogens. We further show that phage can identify pathovariant Escherichia coli infections and distinguish between closely-related pathogenic bacteria such as Staphylococcus aureus and frequent contaminants such as coagulase-negative Staphylococcus. Phage DNA may have utility in identifying bacterial pathogens in infection and studying bacterial dynamics.