Unlocking data in Klebsiella lysogens to predict capsular type-specificity of phage depolymerases

Viral entry is a critical step in the infection process. Klebsiella spp. and other clinically relevant bacteria often express complex polysaccharide capsules that act as a barrier to phage entry. In turn, most lytic phages targeting Klebsiella encode depolymerases for capsule removal. This virus-host arms race leads to extensive genetic diversity in both capsules and depolymerases, complicating our ability to understand their interaction. This study exploits the genetic information encoded in Klebsiella prophages to model the interplay between the bacteria, the prophages, and their depolymerases, using a directed acyclic graph and a sequence clustering-based method. Both approaches show significant predictive ability for prophage capsular tropism and, importantly, are transferrable to lytic phages. In addition to creating a comprehensive database linking depolymerase sequences to their specific targets, this study demonstrates the predictability of phage-host interactions at the subspecies level, providing insights for improving the therapeutic and industrial applicability of phages.