Finding the Achilles’ heel of Streptococcus suis : molecular mechanisms of adaptation to host-like environments

This thesis investigates how Streptococcus suis adapts to host environments and identifies vulnerabilities that could inform new antimicrobial strategies. Using transposon mutagenesis and host-derived fluids, we uncovered conditionally essential genes that support growth in activated porcine serum and cerebrospinal fluid, highlighting key roles for purine biosynthesis, membrane homeostasis, and amino acid transport. We then dissected membrane-stress responses and revealed a coordinated regulatory network involving the LiaFSR and two LytTR systems that controls envelope integrity, competence, biofilm formation, and viability in host-like conditions. Epigenetic regulation was explored through two type I restriction–modification systems, showing that interactions between two different methylation systems influence carbohydrate acquisition, central metabolism, and growth, particularly in disease-associated lineages. We also benchmarked Nanopore sequencing for applications requiring precise taxonomic and genetic resolution, improving long-read workflows for microbiome and mutagenesis studies. Together, these findings expose metabolic and regulatory bottlenecks that shape S. suis survival in host niches and provide entry points for antimicrobial discovery.