Ashton Creasy-Marrazzo

Virulent bacteriophages (phages) can kill bacterial prey, potentially reducing burden of infection. In cholera, a high phage to Vibrio cholerae ratio is associated with mild dehydration, yet the relative importance of this ratio in disease severity remains unclear. We used machine learning to rank select host, microbial, and environmental factors as determinants of dehydration severity in over 600 cholera patients from across Bangladesh. We found the phage:pathogen ratio ranked among the top classifiers for mild dehydration, behind age and location. We advocate that phage predation be included as a key factor in cholera characterization for scientific, clinical and epidemiological applications.

Despite an increasingly detailed picture of the molecular mechanisms of phage-bacterial interactions, we lack an understanding of how these interactions evolve and impact disease within patients. Here we report a year-long, nation-wide study of diarrheal disease patients in Bangladesh. Among cholera patients, we quantified Vibrio 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 suppressed V. cholerae to varying degrees and were inversely associated with severe dehydration depending on resistance mechanisms. In the absence of anti-phage defenses, predation was ‘effective,’ with a high predator:prey ratio that correlated with increased genetic diversity among the prey. In the presence of anti-phage defenses, predation was ‘ineffective,’ with a lower predator:prey ratio that correlated with increased genetic diversity among the predators. Phage-bacteria coevolution within patients should therefore be considered in the deployment of phage-based therapies and diagnostics. One Sentence Summary: A survey of cholera patients in Bangladesh identifies phage predation as a biomarker of disease severity and driver of coevolution within patients.