P149 Role of the humoral pattern recognition molecule PTX3 in defence against urinary tract infections

Introduction Urinary tract infections (UTIs), which remain a major public health problem, are mainly caused by uropathogenic strains of Escherichia coli (UPEC). UTIs can progress to acute pyelonephritis that gives rise to severe morbidity. Cellular innate immune receptors and mediators play an important role in defence against UTIs but the role of humoral innate immunity has not been explored. The present study was designed to investigate the role in UTI of the soluble pattern recognition molecule pentraxin 3 (PTX3), a key component of the innate immune system. Methods We monitored the bacterial load and the inflammatory response in kidneys and bladder of Ptx3 +/+ and Ptx3 −/− mice transurethrally infected with UPEC. Bone-marrow chimeric mice were generated to investigate the separate contribution of PTX3 derived from hematopoietic or stromal cells. We assessed whether PTX3 acts as an opsonin, facilitating UPEC phagocytosis. Expression of PTX3 was analysed by ELISA in urine of patients with UTI and in cell supernatants. Finally, we genotyped highly selected UTI prone patients and compared their genotype frequencies in the PTX3 locus with a group of healthy patients. Results UTI of mice with UPEC was associated with increased levels of PTX3 in tissues and blood that correlated with the severity of the infection. PTX3-deficient mice showed a defective capacity to control UTI and increased tissue inflammation and damage. Urothelium is identified as a new source of PTX3 and both hematopoietic cell-derived and stromal cell-derived PTX3 were required for protection against UTI. PTX3 recognised UPEC and PTX3 opsonisation amplified UPEC phagocytosis by murine and human neutrophils. In patients with UTI, disease severity correlated with PTX3 levels in urine. Finally, human counterpart of our animal data were supported by genetic analysis of UTI-prone patients where PTX3 polymorphisms were associated with susceptibility to acute pyelonephritis. Conclusion Our results broaden the repertoire of defence effector molecules in UTI to include the humoral innate molecule PTX3 in mouse and human.