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Cell. Infect. Microbiol."],"abstract":"<jats:p>Our previous work using a murine model of pyelonephritis demonstrated that the C5a\/C5aR1 axis plays a pathogenic role in acute kidney infection. In this study, we report that the 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 \u03b1-mannosyl residues (Man) (a potential ligand for type 1 fimbriae of <jats:italic>E. coli<\/jats:italic>) at the luminal surface of the bladder epithelium and reduced early bacterial colonization of the bladder. <jats:italic>In vitro<\/jats:italic>, C5a stimulation enhanced mannose expression in and facilitated bacterial adhesion\/colonization to human bladder epithelial cells. C5a stimulation also upregulated the activation of ERK1\/2 and NF-\u03baB signaling and gene expression of proinflammatory cytokines (i.e., <jats:italic>Il6, Il1b, Cxcl1, Ccl2<\/jats:italic>) in the epithelial cells, which could drive pro-inflammatory responses leading to tissue injury. Administration of the C5aR1 antagonist effectively reduced bladder bacterial load and tissue injury. Thus, our findings demonstrate a previously unknown pathogenic role for the C5a\/C5aR1 axis in bladder infection and suggest that the 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.<\/jats:p>","DOI":"10.3389\/fcimb.2022.824505","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T14:24:14Z","timestamp":1648650254000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The C5a\/C5aR1 Axis Contributes to the Pathogenesis of Acute Cystitis Through Enhancement of Adhesion and Colonization of Uropathogenic E. coli"],"prefix":"10.3389","volume":"12","author":[{"given":"Kun-Yi","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Xuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue-Ling","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Juan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teng-Yue","family":"Diao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Rong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-Xiu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wuding","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju-Rong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/nri3887","article-title":"The Nature of Immune Responses to Urinary Tract Infections","volume":"15","author":"Abraham","year":"2015","journal-title":"Nat. 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