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TLR Signaling Mediated by MyD88 Is Required for a Protective Innate Immune Response by Neutrophils to Citrobacter rodentium¹

Sarah L. Lebeis^*,, Bettina Bommarius, Charles A. Parkos, Melanie A. Sherman^2,3, and Daniel Kalman^2,3,

^* Microbiology and Molecular Genetics Graduate Program and Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322

Enteropathogenic Escherichia coli, enterohemorrhagic E. coli, and Citrobacter rodentium are classified as attaching and effacing pathogens based on their ability to adhere to intestinal epithelium via actin-filled membranous protrusions (pedestals). Infection of mice with C. rodentium causes breach of the colonic epithelial barrier, a vigorous Th1 inflammatory response, and colitis. Ultimately, an adaptive immune response leads to clearance of the bacteria. Whereas much is known about the adaptive response to C. rodentium, the role of the innate immune response remains unclear. In this study, we demonstrate for the first time that the TLR adaptor MyD88 is essential for survival and optimal immunity following infection. MyD88^–/– mice suffer from bacteremia, gangrenous mucosal necrosis, severe colitis, and death following infection. Although an adaptive response occurs, MyD88-dependent signaling is necessary for efficient clearance of the pathogen. Based on reciprocal bone marrow transplants in conjunction with assessment of intestinal mucosal pathology, repair, and cytokine production, our findings suggest a model in which TLR signaling in hemopoietic and nonhemopoietic cells mediate three distinct processes: 1) induction of an epithelial repair response that maintains the protective barrier and limits access of bacteria to the lamina propria; 2) production of KC or other chemokines that attract neutrophils and thus facilitate killing of bacteria; and 3) efficient activation of an adaptive response that facilitates Ab-mediated clearance of the infection. Taken together, these experiments provide evidence for a protective role of innate immune signaling in infections caused by attaching and effacing pathogens.

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.

¹ This work was supported by the following sources: Emory University URC Pilot Project Award (to M.A.S. and D.K.), Digestive Diseases Research Development Center at Emory University (DK-064399), Digestive Diseases Research Development Center Pilot Award (DK-245310 to M.A.S.), R01-DK-072564 and R01-DK-079392 (to C.A.P.), K01-AR-002157-05 (to M.A.S.), and R01-A1056067-01 (to D.K.).

² Address correspondence and reprint requests to Dr. Daniel Kalman, Department of Pathology and Laboratory Medicine, Emory University, Whitehead Research Building 144, 165 Michael Street, Atlanta, GA 30322; E-mail address: dkalman{at}emory.edu or Dr. Melanie Sherman, Department of Pathology and Laboratory Medicine, Emory University, Whitehead Research Building 143, 165 Michael Street, Atlanta, GA 30322; E-mail address: msherma{at}emory.edu

³ M.A.S. and D.K. contributed equally to this work.

⁴ Abbreviations used in this paper: EPEC, enteropathogenic E. coli; A/E, attaching and effacing; DSS, dextran sodium sulfate; EHEC, enterohemorrhagic E. coli; MLN, mesenteric lymph node; MPO, myeloperoxidase; TIRAP, Toll-IL-1R domain-containing adaptor protein; WT, wild type; p.i., postinfection.

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