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J. Biol. Chem., Vol. 281, Issue 19, 13317-13323, May 12, 2006

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The Role of Decay-accelerating Factor as a Receptor for Helicobacter pylori and a Mediator of Gastric Inflammation^*

Daniel P. O'Brien, Dawn A. Israel, Uma Krishna, Judith Romero-Gallo, John Nedrud, M. Edward Medof, Feng Lin, Raymond Redline, Douglas M. Lublin^¶, Bogdan J. Nowicki^||, Aime T. Franco, Seth Ogden, Amanda D. Williams, D. Brent Polk, and Richard M. Peek, Jr.^**1

From the Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279, the Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, the ^¶Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, the ^||Departments of Obstetrics & Gynecology and Biomedical Sciences and Division of Microbial Pathogenesis and Immune Response, Meharry Medical Center, Nashville, Tennessee 37208, and the ^**Department of Veterans Affairs Medical Center, Nashville, Tennessee 37212

Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for peptic ulcer disease and distal gastric adenocarcinoma, a process for which adherence of H. pylori to gastric epithelial cells is critical. Decay-accelerating factor (DAF), a protein that protects epithelial cells from complement-mediated lysis, also functions as a receptor for several microbial pathogens. In this study, we investigated whether H. pylori utilizes DAF as a receptor and the role of DAF within H. pylori-infected gastric mucosa. In vitro studies showed that H. pylori adhered avidly to Chinese hamster ovary cells expressing human DAF but not to vector controls. In H. pylori, disruption of the virulence factors vacA, cagA, and cagE did not alter adherence, but deletion of DAF complement control protein (CCP) domains 1-4 or the heavily O-glycosylated serine-threonine-rich COOH-terminal domain reduced binding. In cultured gastric epithelial cells, H. pylori induced transcriptional up-regulation of DAF, and genetic deficiency of DAF attenuated the development of inflammation among H. pylori-infected mice. These results indicate that DAF may regulate H. pylori-epithelial cell interactions relevant to pathogenesis.

Received for publication, February 24, 2006

^* This work was supported in part by National Institutes of Health Grants DK-58587 and CA-77955 (to R. M. P.) and by the Medical Research Service of the Department of Veterans Affairs (to R. M. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: Division of Gastroenterology, Vanderbilt University School of Medicine, 2215 Garland Ave., 1030C MRB IV, Nashville, TN 37232-2279. Tel.: 615-322-5200; Fax: 615-343-6229; E-mail: richard.peek{at}vanderbilt.edu.

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