Synergy between type 1 fimbriae expression and C3 opsonisation increases internalisation of E. coli by human tubular epithelial cells

<p>Abstract</p> <p>Background</p> <p>Bacterial infection of the urinary tract is a common clinical problem with <it>E. coli </it>being the most common urinary pathogen. Bacterial uptake into epithelial cells is increasingly recognised as an important feature of infection. Bacterial virulence factors, especially fimbrial adhesins, have been conclusively shown to promote host cell invasion. Our recent study reported that C3 opsonisation markedly increases the ability of <it>E. coli </it>strain J96 to internalise into human proximal tubular epithelial cells via CD46, a complement regulatory protein expressed on host cell membrane. In this study, we further assessed whether C3-dependent internalisation by human tubular epithelial cells is a general feature of uropathogenic <it>E. coli </it>and investigated features of the bacterial phenotype that may account for any heterogeneity.</p> <p>Results</p> <p>In 31 clinical isolates of <it>E. coli </it>tested, C3-dependent internalisation was evident in 10 isolates. Type 1 fimbriae mediated-binding is essential for C3-dependent internalisation as shown by phenotypic association, type 1 fimbrial blockade with soluble ligand (mannose) and by assessment of a type 1 fimbrial mutant.</p> <p>Conclusion</p> <p>we propose that efficient internalisation of uropathogenic <it>E. coli </it>by the human urinary tract depends on co-operation between type 1 fimbriae-mediated adhesion and C3 receptor -ligand interaction.</p

Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury.

Physiochemical stress induces tissue injury as a result of the detection of abnormal molecular patterns by sensory molecules of the innate immune system. Here, we have described how the recently discovered C-type lectin collectin-11 (CL-11, also known as CL-K1 and encoded by COLEC11) recognizes an abnormal pattern of L-fucose on postischemic renal tubule cells and activates a destructive inflammatory response. We found that intrarenal expression of CL-11 rapidly increases in the postischemic period and colocalizes with complement deposited along the basolateral surface of the proximal renal tubule in association with L-fucose, the potential binding ligand for CL-11. Mice with either generalized or kidney-specific deficiency of CL-11 were strongly protected against loss of renal function and tubule injury due to reduced complement deposition. Ex vivo renal tubule cells showed a marked capacity for CL-11 binding that was induced by cell stress under hypoxic or hypothermic conditions and prevented by specific removal of L-fucose. Further analysis revealed that cell-bound CL-11 required the lectin complement pathway-associated protease MASP-2 to trigger complement deposition. Given these results, we conclude that lectin complement pathway activation triggered by ligand-CL-11 interaction in postischemic tissue is a potent source of acute kidney injury and is amenable to sugar-specific blockade

Protective role for collectin‐11 in rheumatoid arthritis in mice

OBJECTIVE. Collectin-11 (CL-11) is a soluble C-type lectin, a mediator of innate immunity. Its role in autoimmune disorders is unknown. The goal of this study was to determine the role of CL-11 in a mouse model of rheumatoid arthritis (RA). METHODS. A murine collagen-induced arthritis (CIA) model, combining both gene deletion of Colec11 and recombinant (rCL-11) treatment approaches were employed. Joint inflammation and tissue destruction, circulating levels of inflammatory cytokines and adaptive immune responses were assessed in CIA mice. Splenic CD11c(+) cells were used to examine the influence of CL-11 on antigen presenting cell (APC) function. Serum levels of CL-11 in RA patients were also examined. RESULTS. Colec11(−/−) mice developed more severe arthritis than WT mice (as determined by disease incidence, clinical arthritis scores and histopathology; P<0.05). Disease severity is associated with significantly enhanced APC activation, Th1/Th17 responses, pathogenic IgG2a production and joint inflammation, as well as elevated circulating levels of inflammatory cytokines. In vitro analysis of CD11c(+) cells revealed that CL-11 is critical for suppression of APC activation and function. Pharmacological treatment of mice with rCL-11 reduced the severity of CIA in mice. Analysis of human blood samples revealed that serum levels of CL-11 was lower in RA patients (n=51) compared to healthy controls (n=53), a serum CL-11 reduction also displays a negative relationship with DAS28, ESR and CRP (P<0.05). CONCLUSION. Our findings demonstrate a novel role for CL-11 in protection against RA, suggesting the underlying mechanism involved suppression of APC activation and subsequent T cell responses

Complement in organ transplantation

PURPOSE OF REVIEW: The aim of this review is to bring to attention the most recent advances made in understanding the role of complement components in both innate and adaptive immune responses in solid organ transplantation with emphasis on the kidney. RECENT FINDINGS: Alongside recent findings related to the role of anaphylatoxins in modulating adaptive immune responses, there has been a genomic study to assess the expression of inflammatory markers in kidney transplantation, showing significant involvement of some complement molecules in predicting graft function. Modulators of complement pathway activity such as Decay Accelerating factor (CD55) and CD59 have also been shown to have a role in graft rejection. Potential new therapeutic targets related to complement proteins are being investigated. SUMMARY: The mechanism of rejection in solid organ transplantation is influenced by the initial inflammatory response and subsequent adaptive alloimmune response, both of which have been shown to be affected by various complement components. Due to limitations of existing treatments, new approaches are needed to better control these responses to improve graft survival. Built on an expanding knowledge of complement involvement, targeted blocking of the effector complement molecules and modulating the expression of complement inhibitors has suggested potentially useful approaches for reducing the effect of inflammatory damage from cold ischaemia as well as reducing the activation of the adaptive immune system related to complement