Vibrio parahaemolyticus metabolically adapts while tempering the host immune response during host cell invasion.

Vibrio parahaemolyticus (V. para) is an enteric pathogen that establishes a protected intracellular niche using its second type III secretion system. However, how this bacterium adapts to the host cytoplasm while overcoming cellular defenses has remained unclear. To define these mechanisms, we performed dual-transcriptomic profiling of both pathogen and host during invasion, intracellular replication, and late infection. Our analyses revealed extensive metabolic reprogramming by V. para, including induction of diverse nutrient transporters and metabolic pathways. We discovered that because mammalian cells are auxotrophic for aromatic amino acids, V. para must activate its own unique biosynthetic machinery, a requirement that proved essential for intracellular growth. Infected host cells mounted a sustained NF-kappaB response. Both heightened NF-kappaB activation and disruption of canonical NF-kappaB signaling restricted bacterial expansion, indicating that V. para exploits a finely tuned Goldilocks level of immune signaling to promote survival and replication. Together, these findings uncover fundamental metabolic and immune adaptations that drive pathogenesis.