Breaking CHIPS-Mediated immune evasion with tripterin to promote neutrophil chemotaxis against MRSA infection

Neutrophils are the most important innate immune cells in host defense against methicillin-resistant Staphylococcus aureus (MRSA). However, MRSA orchestrates precise and timely expression of a series of virulence factors, especially the chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS), to evade neutrophil-mediated host defenses. Here, we demonstrated that tripterin, a plant-derived bioactive pentacyclic triterpenoid, had a low minimum inhibitory concentration (MIC) of 1.28 µg/mL and displayed excellent anti-MRSA activity in vitro and in vivo. RNA-seq and further knockdown experiments revealed that tripterin could dramatically downregulate the expression of CHIPS by regulating the SaeRS two-component regulatory system, thereby enhancing the chemotactic response of neutrophils. Furthermore, tripterin also displayed a potential inhibitory effect on biofilm components to enhance neutrophil infiltration into the interior of the biofilm. In a mouse bacteremia model, tripterin could still maintain an excellent therapeutic effect that was significantly better than that of the traditional Antibiotic vancomycin. Overall, these results suggest that tripterin possesses a superior Antibacterial activity via breaking CHIPS-mediated immune evasion to promote neutrophil chemotaxis, thus providing a novel strategy for combating serious pathogenic infections.

CHIPS; Host defense; Methicillin-resistant Staphylococcus aureus; Neutrophil; Tripterin.