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This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0902029v1 183/10/6588    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Mittal, R. Articles by Prasadarao, N. V. PubMed PubMed Citation Articles by Mittal, R. Articles by Prasadarao, N. V.

Enterobacter sakazakii Targets DC-SIGN to Induce Immunosuppressive Responses in Dendritic Cells by Modulating MAPKs¹

Rahul Mittal,^* Silvia Bulgheresi, Claudia Emami, and Nemani V. Prasadarao^2*

*Division of Infectious Diseases and Department of Surgery, The Saban Research Institute, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA 90027; and Faculty of Life Sciences, Department of Marine Biology, University of Vienna, Austria

Enterobacter sakazakii (ES) is an emerging pathogen that causes meningitis and necrotizing enterocolitis in infants. Dendritic cells (DCs) are professional phagocytic cells that play an essential role in host defense against invading pathogens; however, the interaction of ES with DCs is not known. In this study, we demonstrate that ES targets DC-specific ICAM nonintegrin (DC-SIGN) to survive in myeloid DCs for which outer membrane protein A (OmpA) expression in ES is critical, although it is not required for uptake. In addition, DC-SIGN expression was sufficient to cause a significant invasion by ES in HeLa cells and intestinal epithelial cells, which are normally not invaded by ES. OmpA⁺ ES prevented the maturation of DCs by triggering the production of high levels of IL-10 and TGF-β and by suppressing the activation of MAPKs. Pretreatment of DCs with Abs to IL-10 and TGF-β or of bacteria with anti-OmpA Abs significantly enhanced the maturation markers on DCs. Furthermore, DCs pretreated with various inhibitors of MAPKs prohibited the increased production of proinflammatory cytokines stimulated by LPS or OmpA^– ES. LPS pretreatment followed by OmpA⁺ ES infection of DCs failed to induce maturation of DCs, indicating that OmpA⁺ ES renders the cells in immunosuppressive state to external stimuli. Similarly, OmpA⁺ ES-infected DCs failed to present Ag to T cells as indicated by the inability of T cells to proliferate in MLR. We conclude that ES interacts with DC-SIGN to subvert the host immune responses by disarming MAPK pathway in DCs.

² Address correspondence and reprint requests to Dr. Nemani V. Prasadarao, Division of Infectious Diseases, MS #51, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027. E-mail address: pnemani{at}chla.usc.edu

¹ This work was supported by National Institutes of Health Grant AI40567 (to N.V.P.) and by the Austrian Science Fund (FWF) Grant P17710-B12 (to S.B.).