Phage predation and antibiotic exposure are inversely associated with disease severity and shape pathogen genetic diversity in cholera patients

Madi, N.; Cato, E. T.; Sayeed, M. A.; Islam, K.; Khabir, M. I. U.; Bhuiyan, M. T. R.; Begum, Y.; Rashid, M. M.; Creasy-Marrazzo, A.; Brinkley, L.; Kamat, M.; Cuenod, A.; Bailey, L. S.; Basso, K. B.; Qadri, F.; Khan, A. I.; Shapiro, B. J.; Nelson, E. J.

doi:10.1101/2023.06.14.544933

bioRxiv · 10.1101/2023.06.14.544933

Phage predation and antibiotic exposure are inversely associated with disease severity and shape pathogen genetic diversity in cholera patients

Madi, N.·Cato, E. T.·Sayeed, M. A.·Islam, K.·Khabir, M. I. U.·Bhuiyan, M. T. R.·Begum, Y.·Rashid, M. M.·Creasy-Marrazzo, A.·Brinkley, L.·Kamat, M.·Cuenod, A.·Bailey, L. S.·Basso, K. B.·Qadri, F.·Khan, A. I.·Shapiro, B. J.·Nelson, E. J.

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Abstract

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 SummaryA survey of cholera patients in Bangladesh identifies phage predation as a biomarker of disease severity and driver of coevolution within patients.

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Madi, N., Cato, E. T., Sayeed, M. A., Islam, K., Khabir, M. I. U., Bhuiyan, M. T. R., Begum, Y., Rashid, M. M., Creasy-Marrazzo, A., Brinkley, L., Kamat, M., Cuenod, A., Bailey, L. S., Basso, K. B., Qadri, F., Khan, A. I., Shapiro, B. J., Nelson, E. J.. 2023-06-14. Phage predation and antibiotic exposure are inversely associated with disease severity and shape pathogen genetic diversity in cholera patients. https://doi.org/10.1101/2023.06.14.544933

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