The Co-Evolutionary Arms Race Between Salmonella and the NLRC4 Inflammasome: Immune Recognition and Evasion Strategies

Salmonella is a globally significant foodborne intracellular pathogen, and invasive salmonellosis poses a major global public health threat. The NLR family CARD-containing protein 4 (NLRC4) inflammasome, a pivotal cytosolic innate immune sensor, specifically recognizes Salmonella flagellin and type III secretion system (T3SS) components via the NAIP (NLR family apoptosis inhibitory protein) family. Upon activation, it triggers pyroptosis, pro-inflammatory cytokine release, and infected intestinal epithelial cell extrusion, serving as a central pathway for host defense against Salmonella colonization and systemic spread. This work systematically summarizes the structural composition, activation mechanisms, post-translational modifications, and regulatory protein network of the NLRC4 inflammasome, and highlights the molecular mechanisms by which Salmonella evades NLRC4 surveillance through multiple strategies: transcriptional downregulation of immunogenic ligands, structural modification of T3SS components, secretion of effector proteins, and chemotaxis-virulence synergy. A comprehensive delineation of the co-evolutionary arms race between Salmonella and the NLRC4 inflammasome provides an integrated mechanistic framework for understanding host–pathogen immune interplay. Deciphering the mechanisms of bacterial immune evasion on this basis holds critical importance for identifying novel anti-infective targets and advancing translational preventive and therapeutic strategies against salmonellosis.