Ecological specialization and constrained evolution shape virulence diversity in zoonotic pathogen L. interrogans

Host specialization is central to the emergence of zoonotic pathogens, yet mechanisms shaping bacterial adaptation across diverse hosts remain poorly understood. Leptospira interrogans circulates among an exceptionally broad range of reservoirs, but only serogroup Icterohaemorrhagiae dominates the global burden of human leptospirosis, raising fundamental questions about its ecological and pathogenic success. Here, we integrate a global genomic dataset to dissect host adaptation in L. interrogans. Population genomic analyses reveal that serogroups Icterohaemorrhagiae and Pomona dominate worldwide and display signatures of ecological specialization. These serogroups have followed distinct evolutionary trajectories that are central to host specialization, characterized by extensive divergence in membrane and signaling genes, together with the acquisition of specialized functional repertoires linked to host adaptation. Transcriptomic and proteomic profiling demonstrate that these genomic differences are coupled to distinct regulatory programs, predominantly affecting virulence and stress response. Altogether, these findings demonstrate that intraspecies heterogeneity in L. interrogans emerges from the convergence of genomic constraint, membrane remodeling and regulatory divergence, shaping host specialization and zoonotic pathogenicity.