AUTHOR=Song Yun , Wu Kun-Yi , Wu Weiju , Duan Zhao-Yang , Gao Ya-Feng , Zhang Liang-Dong , Chong Tie , Garstka Malgorzata A. , Zhou Wuding , Li Ke 

TITLE=Epithelial C5aR1 Signaling Enhances Uropathogenic Escherichia coli Adhesion to Human Renal Tubular Epithelial Cells

JOURNAL=Frontiers in Immunology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00949

DOI=10.3389/fimmu.2018.00949

ISSN=1664-3224

ABSTRACT=Recent work in a murine model of ascending urinary tract infection has suggested that C5a/C5aR1 interactions play a pathogenic role in the development of renal infection through enhancement of bacterial adhesion/colonisation to renal tubular epithelial cells (RTEC). In the present study, we extended these observations to human. We show that renal tubular epithelial C5aR1 signalling is involved in promoting uropathogenic E coli (UPEC) adhesion/invasion of host cells. Stimulation of primary cultures of RTEC with C5a resulted in significant increases in UPEC adhesion/invasion of the RTEC. This was associated with enhanced expression of terminal alpha-mannosyl residues (Man) (a ligand for type 1 fimbriae of E coli) in the RTEC following C5a stimulation. Mechanism studies revealed that C5aR1-mediated activation of ERK1/2/NF-ΚB and up-regulation of pro-inflammatory cytokine production (i.e. TNF-alpha) is at least partly responsible for the up-regulation of Man expression and bacterial adhesion. Clinical sample studies showed that C5aR1 and Man were clearly detected in the renal tubular epithelium of normal human kidney biopsies, and UPEC bound to the epithelium in a D-mannose dependent manner. Additionally, C5a levels were significantly increased in urine of UTI patients compared to healthy controls. Our data therefore demonstrate that, in agreement with observations in mice, human renal tubular epithelial C5aR1 signalling can up-regulate Man expression in RTEC, which enhances UPEC adhesion to and invasion of RTEC. It also suggests the in vivo relevance of upregulation of Man expression in renal tubular epithelium by C5a/C5aR1 interactions and its potential impact on renal infection.