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

Abstract

<i>Campylobacter jejuni</i> (<i>C. jejuni</i>) is a leading cause of human gastroenteritis worldwide and must overcome intestinal innate immunity, including antimicrobial peptide LL-37. However, how <i>C. jejuni</i> responds to LL-37 remains unclear. Here, we showed that <i>C. jejuni</i> infection stimulates intestinal epithelial cells to secrete LL-37, exhibiting effective antibacterial activity against 86.3% of <i>C. jejuni</i> 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 <i>htrA</i> 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-37^I20M/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 <i>C. jejuni</i> infection.