Phage predation is a biomarker for disease severity and shapes pathogen genetic diversity in cholera patients

Abstract

AbstractA century has passed since the discovery that virulent bacteriophages are associated with improved survival of cholera patients. Despite an increasingly detailed picture of the molecular mechanisms that govern phage-bacterial interactions, we lack an understanding of how these interactions impact disease severity. Here we report a year-long, nation-wide study of diarrheal disease patients in Bangladesh. Among the subset of cholera patients, we quantifiedVibrio cholerae(prey) and its virulent phages (predators) using metagenomics and quantitative PCR, while accounting for antibiotic exposure using quantitative mass spectrometry. Virulent phage (ICP1) and antibiotics suppressedV. choleraeto varying degrees and were inversely associated with severe dehydration; aspects of these effects were dependent on resistance mechanisms. In the absence of anti-phage defenses, predation was ‘effective’ with a high predator to prey ratio that correlated with increased genetic diversity among the prey. In the presence of anti-phage defenses, predation was ‘ineffective’ with a low predator to prey ratio that correlated with increased genetic diversity among the predators. Our results link phage predation to disease severity, support phage-bacteria coevolution within patients, and suggest the ratio of phage to pathogen can serve as a biomarker for clinical, diagnostic, and epidemiologic applications.One Sentence SummaryA nation-wide prospective study of cholera patients in Bangladesh identifies effective phage predation and antibiotics as markers of disease severity and selective pressures for cognate resistance mechanisms.