Structural Insights to the Pathophysiology of Effector Induced Immunostimulation in Salmonella Typhimurium: Biocomputational Methods.

Introduction: The worldwide impact of the foodborne pathogen Salmonella can never be overstated, nor can be the fatal threat of septicemia in patients infected with its Typhimurium serovar. Behind the hyperimmune response in the case of septicemia lies a critical phenomenon of the bacterial pathogenic signals being sensed by different pattern recognition receptors, such as the Typhimurium effector proteins that are detected by toll-like receptors.

Methods: To mitigate such a threat, precise structural and functional description of these effectors is necessary. The same has been addressed in this article using accelerated biocomputational techniques, beginning with the identification of the functional niche of the effectors and their influence over other proteins.

Results: The molecular crystal structures were retrieved, and rigorous molecular docking experiments were conducted among the TLRs and effector proteins in order to examine the interactions. The interactions were thereby evaluated and screened according to their respective strengths using parameters including binding affinity, dissociation constant, hydropathy variation, etc. SopB effectors were found to be detected by three different TLR proteins and GtgE by two other TLRs, while SifA, SrfJ, and SsaV had only a single interacting TLR partner each. Interestingly, TLR9 presented lower sensitivity towards PAMPs of this bacterium.

Conclusion: Normal modal analyses in combination with atomistic molecular dynamics simulations that tend to imitate natural cytosolic environments reveal stable and consistent interactions and realistic conformations among the effector-bound TLR complexes. The findings open up new avenues for the development of targeted therapies against Salmonella, which could significantly reduce the global burden of this foodborne pathogen.