AUTHOR=Wu Kun-Yi , Cao Bo , Wang Chun-Xuan , Yang Xue-Ling , Zhao Shu-Juan , Diao Teng-Yue , Lin Li-Rong , Zhao Guo-Xiu , Zhou Wuding , Yang Ju-Rong , Li Ke 

TITLE=The C5a/C5aR1 Axis Contributes to the Pathogenesis of Acute Cystitis Through Enhancement of Adhesion and Colonization of Uropathogenic E. coli

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.824505

DOI=10.3389/fcimb.2022.824505

ISSN=2235-2988

ABSTRACT=Our previous work using a murine model of pyelonephritis demonstrated that C5a/C5aR1 axis plays a pathogenic role in acute kidney infection. In this study, we report that C5a/C5aR1 axis also plays a pathogenic role in acute bladder infection. C5aR1 deficient mice had reduced bladder bacterial load and attenuated bladder tissue injury, which is associated with reduced expression of terminal α-mannosyl residues (Man) (a potential ligand for type 1 fimbriae of E. coli) at luminal surface of bladder epithelium and reduced early bacterial colonization of the bladder. In vitro, C5a stimulation enhanced mannose expression in and facilitated bacterial adhesion/colonization to human bladder epithelial cells. C5a stimulation also upregulated activation of ERK1/2 and NF-κB signaling and gene expression of proinflammatory cytokines (i.e., Il6, Il1b, Cxcl1, Ccl2) in the epithelial cells, which could drive pro-inflammatory responses leading to tissue injury. Administration of C5aR1 antagonist effectively reduced bladder bacterial load and tissue injury. Thus, our findings demonstrate a previously unknown pathogenic role for C5a/C5aR1 axis in bladder infection and suggest that C5a/C5aR1 axis-mediated upregulation of Man expression, enhancement of bacterial adhesion/colonization and excessive inflammatory responses contribute to acute bladder infection. These findings improve our understanding of the pathogenesis of bladder infection with therapeutic implications for UTI.