Serine protease HtrA promotesintestinal colonization through degrading antimicrobial peptide LL-37.

Source: PubMed, NCBI / U.S. National Library of Medicine

() is a leading cause of human gastroenteritis worldwide and must overcome intestinal innate immunity, including antimicrobial peptide LL-37. However, howresponds to LL-37 remains unclear. Here, we showed thatinfection stimulates intestinal epithelial cells to secrete LL-37, exhibiting effective antibacterial activity against 86.3% ofclinical isolates by disrupting essential processes required for bacterial survival. A subset of isolates displays intrinsic resistance, enabling successful intestinal colonization. We further identified conserved serine protease HtrA as the key determinant of resistance. Mechanistically, LL-37 exposure activates transcriptional regulator NssR, which up-regulatesexpression. Secreted HtrA cleaves LL-37 at Ile-Valsite, abolishing its antimicrobial activity and promoting bacterial survival. In light of this mechanism, we developed a noncleavable LL-37that displays enhanced antibacterial activity and promotes bacterial clearance in mice. Together, our findings uncover mechanistic insights into interactions between human enteric pathogens and antimicrobial peptides and provide a potential strategy for combatinginfection.