GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336487/primaryOK200OtherSalmonella enterica subsp. enterica serovar TyphiOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336487GEOGSEfalseNative Pathogen-Phage Networks Reveal Multilayered Defense and Gut-Active Antiphage Immunity IIBacteriophages 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.2026/08/31GSE336487GSM9836181GSM9836170GSM9836180GSM9836174GSM9836185GSM9836163GSM9836184GSM9836173GSM9836183GSM9836172GSM9836171GSM9836182GSM9836178GSM9836167GSM9836166GSM9836177GSM9836165GSM9836176GSM9836186GSM9836164GSM9836175GSM9836169GSM9836168GSM983617937144336487Salmonella enterica subsp. enterica serovar Typhi