GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336350/primaryOK200OtherSalmonella enterica subsp. enterica serovar Typhimurium str. D23580Otherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336350GEOGSEfalseNative Pathogen-Phage Networks Reveal Multilayered Defense and Gut-Active Antiphage ImmunityBacteriophages strongly shape pathogen evolution, yet the determinants of phage susceptibility in native bacterial backgrounds, and their consequences within mammalian hosts, remain poorly defined. Here, we mapped >1,000 interactions between 20 diverse Salmonella isolates and 52 wild phages from global disease reservoirs, integrating genome-scale fitness profiling with comparative genomics. Receptor identity and surface phase variation, including Hin-mediated flagellar switching, explained ~67% of phage susceptibility patterns, identifying cell-surface architecture as the major determinant of phage host range in Salmonella. Among resistance phenotypes not explained by surface features, we discovered AppA, a prophage-encoded defense factor that abrogates phage replication within its native host. AppA inhibits phage DNA packaging through functional mimicry of a terminase assembly interface, revealing a previously unrecognized mechanism of phage defense. AppA is expressed under conditions encountered during mammalian infection and suppresses phage expansion in the murine gut, demonstrating that prophage-encoded single-gene defenses can shape infection outcomes in vivo.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 enterica subsp. enterica serovar Typhimurium str. D23580