Serine protease HtrA promotes Campylobacter jejuni intestinal colonization through degrading antimicrobial peptide LL-37.

Campylobacter jejuni (C. jejuni) is a leading cause of human gastroenteritis worldwide and must overcome intestinal innate immunity, including antimicrobial peptide LL-37. However, how C. jejuni responds to LL-37 remains unclear. Here, we showed that C. jejuni infection stimulates intestinal epithelial cells to secrete LL-37, exhibiting effective antibacterial activity against 86.3% of C. jejuni clinical 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-regulates htrA expression. Secreted HtrA cleaves LL-37 at Ile20-Val21 site, abolishing its antimicrobial activity and promoting bacterial survival. In light of this mechanism, we developed a noncleavable LL-37I20M/V21R that 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 combating C. jejuni infection.