Protein-centric mechanisms of typhoidal Salmonella pathogenicity: emerging opportunities for diagnostics and anti-virulence therapeutics.

Typhoidal Salmonella (Salmonella enterica serovars Typhi and Paratyphi A) continue to impose a significant global health burden, particularly in regions characterized by inadequate sanitation and rising antimicrobial resistance. Although recent reviews have comprehensively addressed epidemiology, antimicrobial resistance, vaccination strategies, and host-pathogen interactions, virulence determinants are often described in a pathway-specific manner. Consequently, a cohesive macromolecular framework integrating these determinants remains insufficiently developed. In this review, we adopt a protein-centric perspective to systematically elucidate the molecular and structural architecture underlying typhoidal Salmonella pathogenesis. Diverse virulence determinants, including Type III Secretion System (T3SS) effectors, outer membrane proteins, adhesins, toxin subunits, stress-response regulators, and metabolic proteins, are integrated into a unified structural and functional network in which their three-dimensional architectures, protein-protein interaction interfaces, receptor-binding surfaces, catalytic domains, and active-site configurations collectively govern host-cell invasion, intracellular survival, immune evasion, nutrient acquisition, and systemic dissemination. Furthermore, we present a comparative analysis of S. Typhi and S. Paratyphi A, emphasizing differences in protein repertoires and regulatory adaptations that drive their distinct pathogenic mechanisms. Collectively, these structural insights establish a mechanistic bridge between protein architecture and pathogenic function and identify molecular interfaces, catalytic pockets, and receptor-binding surfaces as opportunities for diagnostics, vaccines, and anti-virulence therapeutics. Integration of structural biology with artificial intelligence-assisted drug discovery, protein engineering, single-cell infection models, and host-directed approaches may further accelerate the development of next-generation interventions against typhoidal Salmonella.