Fang Xie&, Yanan Zan&, Yueling Zhang, Ning Zheng, Qiulong Yan, Wanjiang Zhang, Huihui Zhang, Mingjie Jin, Fuguang Chen, Xinyuan Zhang, Siguo Liu1#*

J Biol Chem. 2019 Oct 16. pii: jbc.RA119.009441. doi: 10.1074/jbc.RA119.009441. [Epub ahead of print]

Abstract

Streptococcus suis is a globally distributed zoonotic pathogen associated with meningitis and septicemia in humans, posing a serious threat to public health. To successfully invade and disseminate within its host, this bacterium must overcome the innate immune system. The antimicrobial peptide LL-37 impedes invading pathogens by directly perforating bacterial membranes and stimulating the immune function of neutrophils, which are the major effector cells against S. suis However, little is known about the biological relationship between S. suis and LL-37 and how this bacterium adapts to and evades LL-37-mediated immune responses. In the present study, using an array of approaches, including enzyme, chemotaxis, and cytokine assays; quantitative RT-PCR; and CD spectroscopy, we found that the cysteine protease ApdS from S. suis cleaves LL-37 and thereby plays a key role in the interaction between S. suis and human neutrophils. S. suis infection stimulated LL-37 production in human neutrophils, and S. suis exposure to LL-37 up-regulated ApdS protease expression in the bacterium. We observed that ApdS targets and rapidly cleaves LL-37, impairing its bactericidal activity against S. suis We attributed this effect to the decreased helical content of the secondary structure in the truncated peptide. Moreover, ApdS rescued S. suis from killing by human neutrophils and neutrophil extracellular traps because LL-37 truncation attenuated neutrophil chemotaxis and inhibited the formation of extracellular traps and production of reactive oxygen species. Altogether, our findings reveal an immunosuppressive strategy of S. suis whereby the bacterium blunts the innate host defenses via ApdS protease-mediated LL-37 cleavage.

Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

LL-37; Streptococcus; Streptococcus suis; antimicrobial peptide (AMP); cathelicidin; chemotaxis; cysteine protease; immune evasion; innate immunity; neutrophil