Pseudomonas aeruginosa two-component system CprRS regulates HigBA expression and bacterial cytotoxicity in response to LL-37 stress

Abstract

Pseudomonas aeruginosa is a highly pathogenic bacterium known for its ability to sense and coordinate the production of virulence factors in response to host immune responses. However, the regulatory mechanisms underlying this process have remained largely elusive. In this study, we investigate the two-component system CprRS in P. aeruginosa and unveil the crucial role of the sensor protein CprS in sensing the human host defense peptide LL-37, thereby modulating bacterial virulence. We demonstrate that CprS acts as a phosphatase in the presence of LL-37, leading to the phosphorylation and activation of the response regulator CprR. The results prove that CprR directly recognizes a specific sequence within the promoter region of the HigBA toxin-antitoxin system, resulting in enhanced expression of the toxin HigB. Importantly, LL-37-induced HigB expression promotes the production of type III secretion system effectors, leading to reduced expression of proinflammatory cytokines and increased cytotoxicity towards macrophages. Moreover, mutations in cprS or cprR significantly impair bacterial survival in both macrophage and insect infection models. This study uncovers the regulatory mechanism of the CprRS system, enabling P. aeruginosa to detect and respond to human innate immune responses while maintaining a balanced virulence gene expression profile. Additionally, this study provides new evidence and insights into the complex regulatory system of T3SS in P. aeruginosa within the host environment, contributing to a better understanding of host-microbe communication and the development of novel strategies to combat bacterial infections.

LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases

“…On the other hand, studies have explored other types of biological activities for AMPs. For example, the only type of cathelicidin-derived AMP in humans, LL-37, has drawn much attention due to its numerous biological activities, including antimicrobial activities, LPS-neutralizing activities, and modulation of immune and inflammatory pathways [ 262 , 263 , 264 , 265 , 266 ]. While LL-37’s mechanisms of antibacterial activity have been reasonably well investigated through biophysical studies, further studies to better understand its other biological roles, such as its effects on immune system function, are essential to fully exploit its potential therapeutic applications and side effects.…”