The enormous diversity of bacteriophages and their bacterial hosts presents a significant challenge to predict which phages infect a focal set of bacteria. Infection is largely determined by complementary – and largely uncharacterized – genetics of adsorption, injection, cell take-over and lysis. Here we present a machine learning approach to predict phage-bacteria interactions trained on genome sequences of and phenotypic interactions amongst 51 Escherichia coli strains and 45 phage l strains that coevolved in laboratory conditions for 37 days. Leveraging multiple inference strategies and without a priori knowledge of driver mutations, this framework predicts both who infects whom and the quantitative levels of infections across a suite of 2,295 potential interactions. We found that the most effective approach inferred interaction phenotypes from independent contributions from phage and bacteria mutations, accurately predicting 86% of interactions while reducing the relative error in the estimated strength of the infection phenotype by 40%. Feature selection revealed key phage l and E. coli mutations that have a significant influence on the outcome of phage-bacteria interactions, corroborating sites previously known to affect phage l infections, as well as identifying mutations in genes of unknown function not previously shown to influence bacterial resistance. The method's success in recapitulating strain-level infection outcomes arising during coevolutionary dynamics may also help inform generalized approaches for imputing genetic drivers of interaction phenotypes in complex communities of phage and bacteria.

Funding provided by: United States Army Research OfficeROR ID: https://ror.org/05epdh915Award Number: W911NF1910384 Funding provided by: National Science FoundationROR ID: https://ror.org/021nxhr62Award Number: 2200269 Funding provided by: NIH Common FundROR ID: https://ror.org/001d55x84Award Number: R01 AI146592 Funding provided by: Simons FoundationROR ID: https://ror.org/01cmst727Award Number: 930283 Funding provided by: Howard Hughes Medical InstituteROR ID: https://ror.org/006w34k90Award Number: 311169