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Systematic Discovery of Salmonella Phage-Host Interactions via High-Throughput Genome-Wide Screens

View ORCID ProfileBenjamin A. Adler, Crystal Zhong, Hualan Liu, Elizabeth Kutter, Adam M. Deutschbauer, View ORCID ProfileVivek K. Mutalik, View ORCID ProfileAdam P. Arkin
doi: https://doi.org/10.1101/2020.04.27.058388
Benjamin A. Adler
1The UC Berkeley-UCSF Graduate Program in Bioengineering, Berkeley, California, United States
2Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States
3Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States
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  • ORCID record for Benjamin A. Adler
Crystal Zhong
2Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States
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Hualan Liu
5Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States
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Elizabeth Kutter
4The Evergreen State College, Olympia, Washington, United States
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Adam M. Deutschbauer
5Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States
6Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California, United States
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Vivek K. Mutalik
3Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States
5Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States
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  • For correspondence: vkmutalik@lbl.gov aparkin@lbl.gov
Adam P. Arkin
2Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States
3Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States
5Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States
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  • For correspondence: vkmutalik@lbl.gov aparkin@lbl.gov
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Abstract

Salmonella species comprise a chronic threat to human health, with over 1.35 million infections and 420 deaths occurring in the US per year due to non-typhoidal, foodborne Salmonella infection. With the rise of antimicrobial resistant (AMR) infections, it is imperative to develop alternative prevention and treatment strategies, such as utilization of lytic bacteriophage as pathogen countermeasures. However, phage-host interactions remain poorly understood, impeding widespread practice. Here, we employed high-throughput, functional analyses to discover the genetic determinants of phage-host interactions between a model enteric Salmonella species, Salmonella enterica serovar Typhimurium (S. typhimurium) and its phages. To rapidly assess genetic contributions to phage sensitivity, we created a 66,996 member randomly barcoded transposon (RB-TnSeq) library in S. typhimurium MS1868. Using this library, we compared fitness across eleven diverse lytic Salmonella phages. Consistent with other loss of function studies against bacteriophage predation, this approach efficiently identified receptors essential to adsorption as well as their regulation. While many of the tested phages bound directly to the lipopolysaccharide (LPS) layer, we report a highly resolved view of differential structural LPS layer requirements for diverse Salmonella phages, including novel adsorption strategies. We also uncover unique routes to phage resistance, including phage-specific metabolic requirements, ion flow, and global transcription factor interplay, difficult to find through traditional approaches. constitutes a major challenge and opportunity. We highlight several examples of how the scale of barcoded screens allowed systems-level hypotheses to be efficiently formulated. These include discovery of a number of cases of cross-resistance and collateral sensitivity among the diverse phage tested. We anticipate that the phage-resistance landscape presented here will faciliate better design of phage-based biocontrol treatments and phage-antibiotic combination therapies.

Competing Interest Statement

V.K.M., A.M.D., and A.P.A. consult for and hold equity in Felix Biotechnology Inc..

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 28, 2020.
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Systematic Discovery of Salmonella Phage-Host Interactions via High-Throughput Genome-Wide Screens
Benjamin A. Adler, Crystal Zhong, Hualan Liu, Elizabeth Kutter, Adam M. Deutschbauer, Vivek K. Mutalik, Adam P. Arkin
bioRxiv 2020.04.27.058388; doi: https://doi.org/10.1101/2020.04.27.058388
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Systematic Discovery of Salmonella Phage-Host Interactions via High-Throughput Genome-Wide Screens
Benjamin A. Adler, Crystal Zhong, Hualan Liu, Elizabeth Kutter, Adam M. Deutschbauer, Vivek K. Mutalik, Adam P. Arkin
bioRxiv 2020.04.27.058388; doi: https://doi.org/10.1101/2020.04.27.058388

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