Evaluating and targeting C5a receptor in pyelonephritis

Lead Research Organisation: King's College London
Department Name: Immunology Infection and Inflam Diseases

Abstract

Urinary tract infection (UTI) caused by the microbe E. coli is a common infectious disease. It is especially frequent in women and children and is a particular problem for patients with diabetes and renal transplants. Although antibiotics can be used to treat the disease, frequent recurrence or persistence of infection is still a big problem. A better understanding of how bacteria are able to invade, survive and grow in the urinary tract, and the mean(s) by which they cause tissue damage is required for improving current treatment. The inflammatory mediators generated in our body in response to infection play essential roles in the first line of host defense against pathogens; however, they can also cause harm when present in excess or are dysregulated. C5a is a potent inflammatory mediator which has been shown to be associated with various inflammatory and infectious diseases. The proposed research is to work out if and how C5a could participate in the development of kidney and bladder infection and contribute to the recurrence or persistence of infection. If we are successful in showing how C5a acts on different cell types within the urinary tract tissues to promote bacteria invasion, survival and growth, this may offer a valuable means to block the action of C5a and thus prevent and treat UTI.

Technical Summary

Urinary tract infection (UTI) caused by uropathogenic E. coli is one of the most common diseases that have the characteristics of frequent recurrence or persistence of infection. In a severe form, it can result in renal failure, chronic kidney disease and death from overwhelming sepsis. Complement, an integral part of the innate immune system, has been described as a double-edged sword since it defends the host against infection, but can also cause harm when activated in an uncontrolled manner. Our previous studies have shown that not only are most human uropathogenic E. coli strains resistant to complement mediated killing, but that complement deficiency in fact protected mice from the development of renal infection. This suggests that the role of complement in UTI is an overwhelmingly damaging one. Given that C5a, a potent inflammatory peptide generated by complement activation, has been implicated in the pathogenesis of various inflammatory and infectious diseases, together with our preliminary data, we hypothesise that C5a is a significant pathogenic mediator in UTI. The proposed research will investigate if and how C5a contributes to the pathogenesis of UTI and explore the therapeutic potential for preventing and treating resistant UTI by targeting C5a receptor (C5aR). To accomplish this, we will employ a murine model of ascending UTI induced by human uropathogenic E. coli, C5aR knockout (C5aR-/-) mice, bone narrow (BM)-chimeras (where the mice have C5aR only on renal parenchymal cells or on BM-derived migratory cells), C5aR ligand (C5a), C5aR antagonist (C5aRa), purified neutrophils and primary renal tubular epithelial cells in our studies. Using these tools, we intend to: i) determine if the absence of C5aR signalling in receptor-deficient or ?blocked mice protects from acute pyelonephritis (APN) and bladder inflammation; ii) investigate the impact of C5aR signalling on epithelial and leukocyte dysfunction and its influence on APN; iii) to build a therapeutic strategy by evaluating the effect of C5aRa given via the urethra into the bladder. We envisage that this study will define a previously unrecognised pathogenic role for C5a in renal infection and provide the mechanistic information about this role, namely that excessive C5a generated during UTI, through acting on C5aR in renal parenchymal cells and infiltrating neutrophils, contribute to tissue destruction, bacterial entry and impairment of resolving bacterial infection. We also see this proposal providing essential background information to pursue novel therapeutic approaches to prevent and treat UTI.
 
Description The role of C3a/C3aR in pylonephritis 
Organisation Xi'an Jiaotong University
Department Core Research Laboratory
Country China 
Sector Academic/University 
PI Contribution Help with experimental design and interpretation of results
Collaborator Contribution Performing experiments
Impact Work in progress
Start Year 2012