Comparative Genomics Reveals Key Adaptive Mechanisms in Pathogen Host-Niche Specialization

Menglu Zhang¹Longxi Han²Caizhi Liao³Weiheng Su¹Chunlai Jiang^1*

• ¹National Engineering Laboratory of AIDS Vaccine, School of life science, Jilin University, Changchun, China
• ²Department of Thoracic Surgery, First Hospital of Tsinghua University, Beijing, China
• ³Clinical Laboratory, The fourth People's Hospital of Jinan, Jinan, China

Understanding the key factors that enable bacterial pathogens to adapt to new hosts is crucial, as host-microbe interactions not only influence host health but also drive bacterial genome diversification, thereby enhancing pathogen survival in various ecological niches. A comparative genomic analysis of 4,366 high-quality human pathogen genomes isolated from diverse hosts and environments was conducted to understand bacterial adaptation mechanisms. Using bioinformatics databases and machine learning approaches, we examined genomic differences in functional categories, virulence factors, and antibiotic resistance genes across various ecological niches. Results revealed significant variability in adaptive strategies of bacterial genomes, with different taxa showing differential enrichment of functional genes depending on the host environment. Human-associated bacteria, particularly from the phylum Pseudomonadota, exhibited higher detection rates of carbohydrate-active enzyme genes and virulence factors related to immune modulation and adhesion, indicating co-evolution with the human host. In contrast, bacteria from environmental sources, particularly those from the phyla Bacillota and Actinomycetota, showed greater enrichment in genes related to metabolism and transcriptional regulation, highlighting their high adaptability to diverse environments. Bacteria from clinical settings had higher detection rates of antibiotic resistance genes, particularly those related to fluoroquinolone resistance. Animal hosts were identified as important reservoirs of resistance genes. Key host-specific bacterial genes, such as hypB, were found to potentially play crucial roles in regulating metabolism and immune adaptation in human-associated bacteria. This study provides new insights into the genetic basis of pathogen adaptation to various ecological niches, offering important evidence for controlling pathogen transmission, improving infection management, and enhancing antibiotic stewardship.