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While a large variety of anti- phage defense mechanisms has been characterized, how expression of these systems is distributed across individual cells and how their combined activities translate into protection from phages has not been studied. Using bacterial single-cell RNA sequencing, we profiled the transcriptomes of \u223c50,000 cells from cultures of a human pathobiont,\n                  <jats:italic>Bacteroides fragilis,<\/jats:italic>\n                  infected with a lytic bacteriophage. We quantified the asynchronous progression of phage infection in single bacterial cells and reconstructed the infection timeline, characterizing both host and phage transcriptomic changes as infection unfolded. We discovered a subpopulation of bacteria that remained uninfected and determined the heterogeneously expressed host factors associated with protection. Each cell\u2019s vulnerability to phage infection was defined by combinatorial phase-variable expression of multiple genetic loci, including capsular polysaccharide (CPS) biosynthesis pathways, restriction-modification systems (RM), and a previously uncharacterized operon likely encoding fimbrial genes. By acting together, these heterogeneously expressed phase-variable systems and anti-phage defense mechanisms create a phenotypic landscape where distinct protective combinations enable the survival and re-growth of bacteria expressing these phenotypes without acquiring additional mutations. The emerging model of complementary action of multiple protective mechanisms heterogeneously expressed across an isogenic bacterial population showcases the potent role of phase variation and stochasticity in bacterial anti-phage defenses.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    Combinatorial phenotypic states with differential vulnerability to phage infection across a\n                    <jats:italic>Bacteroides fragilis<\/jats:italic>\n                    population enable a small number of super-resistant bacterial cells to evade the phage without the need for acquiring mutations.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.13.632860","type":"posted-content","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T04:40:28Z","timestamp":1736916028000},"source":"Crossref","is-referenced-by-count":4,"title":["Combinatorial phenotypic landscape enables bacterial resistance to phage infection"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3265-5664","authenticated-orcid":false,"given":"Anika","family":"Gupta","sequence":"first","affiliation":[{"name":"Institute for Systems Biology, Seattle, WA, USA"},{"name":"Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8090-295X","authenticated-orcid":false,"given":"Norma","family":"Morella","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6834-4246","authenticated-orcid":false,"given":"Dmitry","family":"Sutormin","sequence":"additional","affiliation":[{"name":"Institute for Systems Biology, Seattle, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naisi","family":"Li","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8035-5137","authenticated-orcid":false,"given":"Karl","family":"Gaisser","sequence":"additional","affiliation":[{"name":"Institute for Systems Biology, Seattle, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Robertson","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"name":"Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaroslav","family":"Ispolatov","sequence":"additional","affiliation":[{"name":"Department of Physics, Center for Interdisciplinary Research in Astrophysics and Space Science, University of Santiago, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3163-8782","authenticated-orcid":false,"given":"Georg","family":"Seelig","sequence":"additional","affiliation":[{"name":"Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA, USA"},{"name":"Department of Electrical and Computer Engineering, University of Washington, Seattle, WA, USA"},{"name":"Paul G. 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