Local inflammation induces complement crosstalk which amplifies the antimicrobial response

Jing Zhang, Jingyun Koh, Jinhua Lu, Steffen Thiel, Benjamin S H Leong, Sunil Sethi, Cynthia Y X He, Bow Ho, Jeak L Ding

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    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; CRPratioL-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 CRPratioL-ficolin interaction in a pH- and calcium-sensitive manner. We conclude that the infection-induced local inflammatory conditions trigger a strong interaction between CRPratioL-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.
    Original languageEnglish
    JournalP L o S Pathogens
    Volume5
    Issue1
    Pages (from-to)e1000282
    ISSN1553-7366
    DOIs
    Publication statusPublished - 2009

    Keywords

    • Blood Bactericidal Activity
    • C-Reactive Protein
    • Calcium
    • Complement C1q
    • Complement C3
    • Complement C4
    • Complement Pathway, Classical
    • Complement Pathway, Mannose-Binding Lectin
    • Data Interpretation, Statistical
    • Host-Pathogen Interactions
    • Humans
    • Hydrogen-Ion Concentration
    • Inflammation
    • Lectins
    • Phagocytosis
    • Pseudomonas Infections
    • Pseudomonas aeruginosa

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