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.

Membrane Permeabilization by Trypanosome Lytic Factor, a Cytolytic Human High Density Lipoprotein

“…The obvious impediment to this scenario is the neutral pH of the internal milieu. However, it is known that locally, acidic conditions occur, and that antimicrobial responses are amplified at sites of inflammation (43)(44)(45)(46).…”

Secreted M-Ficolin Anchors onto Monocyte Transmembrane G Protein-Coupled Receptor 43 and Cross Talks with Plasma C-Reactive Protein to Mediate Immune Signaling and Regulate Host Defense

“…Similar to TLRs (2), C-type lectins (CLs) are essential in recognizing pathogens and alerting the host to elicit immune responses against bacterial (3), fungal (4), and viral infections (5). Being structurally and functionally conserved (6), CLs bind to the sugar moieties of pathogen-associated molecular patterns (PAMPs) displayed on microbes (7), activate complements (8,9), promote phagocytosis (10), and induce cytokines (11). Whereas transmembrane CLs including dectins (12) and DC-SIGN (13) have been reported to induce signaling pathways through their cytoplasmic domains, little is known about soluble CLs, which encompass a large family of proteins and alert the host cells to an infection, although mannose binding lectin, which is also a soluble CL, was observed to enhance the proinflammatory response to Staphylococcus aureus independent of complement activation (14).…”

“…M-ficolin is the only ficolin isoform secreted by immune cells such as monocytes (18), neutrophils (19), and alveolar epithelial cells (20). Whereas the mouse homologues of L-or H-ficolins are evolutionarily divergent (21), the M-ficolin gene is well conserved in invertebrates (22), mouse (21), and human (9), suggesting the crucial and fundamental roles of M-ficolin. However, their varied locations in assorted tissues and species are suggestive of their differential functions.…”

“…At the initial phase of infection, the physiological condition of pH 7.4 exists (9). Subsequently, mild acidosis (pH 6.5) can occur at the local site of infection or in a severe systemic infection, due to the massive infiltration of immune cells to the site of infection, which activates the respiratory burst (27,28).…”

“…Therefore, it was of interest to study the potential effects of pH change induced by infection on the functions of M-ficolin. Recently, we found that C-reactive protein (CRP), an acute-phase pentraxin, interacts with circulating L-ficolin at low pH condition (9), thus boosting the immune response during an infection. With 80% homology to L-ficolin, we envisage that M-ficolin and CRP might also interact at the later phase of infection where local acidosis occurs, with potential implications for the regulation of the immune response.…”