Local Inflammation Induces Complement Crosstalk Which Amplifies the Antimicrobial Response

Abstract

By eliciting inflammatory responses, the human immunosurveillance system notably combats invading pathogens, during which acute phase proteins (CRP and cytokines) are elevated markedly. However, the Pseudomonas aeruginosa is a persistent opportunistic pathogen prevalent at the site of local inflammation, and its acquisition of multiple antibiotic-resistance factors poses grave challenges to patient healthcare management. Using blood samples from infected patients, we demonstrate that P. aeruginosa is effectively killed in the plasma under defined local infection-inflammation condition, where slight acidosis and reduced calcium levels (pH 6.5, 2 mM calcium) typically prevail. We showed that this powerful antimicrobial activity is provoked by crosstalk between two plasma proteins; CRP∶L-ficolin interaction led to communication between the complement classical and lectin pathways from which two amplification events emerged. Assays for C4 deposition, phagocytosis, and protein competition consistently proved the functional significance of the amplification pathways in boosting complement-mediated antimicrobial activity. The infection-inflammation condition induced a 100-fold increase in CRP∶L-ficolin interaction in a pH- and calcium-sensitive manner. We conclude that the infection-induced local inflammatory conditions trigger a strong interaction between CRP∶L-ficolin, eliciting complement-amplification pathways which are autonomous and which co-exist with and reinforce the classical and lectin pathways. Our findings provide new insights into the host immune response to P. aeruginosa infection under pathological conditions and the potential development of new therapeutic strategies against bacterial infection. An opportunistic pathogen, Pseudomonas aeruginosa causes local inflammation in various tissues and is an important cause of hospital-acquired infections. While this may manifest as a hot-tub rash, failure to limit such localized inflammation may cause life-threatening septic shock to ensue, leading to multiple organ failure and possibly death. Effective treatment with antibiotics is complicated by the increasing prevalence of multidrug-resistant P. aeruginosa. In this study, we demonstrated that under typical local infection-inflammation conditions of slight acidosis and reduced calcium levels in the blood, P. aeruginosa is killed effectively. This is because such a milieu provokes crosstalk between two proteins involved in host defense, CRP and L-ficolin, which triggers communication between antimicrobial complement pathways that were previously presumed independent of each other. The CRP∶L-ficolin interaction amplifies their antimicrobial activity and enhances bacterial clearance. Insights gained from this host–pathogen interaction mechanism offer fresh perspectives on the potential development of complement immune therapies to enhance eradication of the invading pathogen.