An ensemble pipeline, PhageHost, for phage tail fiber discovery and accurate Klebsiella pneumoniae host prediction...

The high specificity of phages toward their hosts holds great promise for phage therapy while posing a challenge to computational prediction approaches. To this end, we introduce PhageHost (P&H), an ensemble pipeline for large-scale discovery of phage tail fibers and strain-level host prediction in Klebsiella pneumoniae using protein language models (PLMs). The pipeline begins with TailSeek, a PLM for tail fiber detection from phage and prophage genomes. Building on TailSeek predictions, we developed HostBuster, a deep learning framework that integrates tail fiber features with host-specific information to predict the lytic potential of phage-K. pneumoniae pairs. In silico and experimental validations confirm that P&H achieves high sensitivity and precision in both tail fiber identification and host prediction. Moreover, our framework demonstrates strong generalizability, enabling large-scale mining of tail fibers from prophage data across diverse bacterial taxa. P&H significantly accelerates high-throughput phage screening, offering a scalable tool for clinical phage therapy applications.