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Outer Membrane Protein A Expression in Escherichia coli K1 Is Required to Prevent the Maturation of Myeloid Dendritic Cells and the Induction of IL-10 and TGF-β¹

Rahul Mittal^* and Nemani V. Prasadarao^2,*,

^* Division of Infectious Diseases, Saban Research Institute, Childrens Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, CA 90027

Dendritic cells (DCs) are professional APCs that direct both cellular and humoral immune responses. Escherichia coli K1 causes meningitis in neonates; however, the interactions between this pathogen and DCs have not been previously explored. In the present study, we observed that E. coli K1, expressing outer membrane protein A (OmpA), was able to enter, survive, and replicate inside DCs, whereas OmpA^– E. coli was killed within a short period. Opsonization of OmpA⁺ E. coli either with adult or cord serum did not affect its survival inside DCs. Exposure of DCs to live OmpA⁺ E. coli K1 prevented DCs from progressing in their maturation process as indicated by failure to up-regulate costimulatory molecules, CD40, HLA-DR, and CD86. The distinct DC phenotype requires direct contact between live bacteria and DCs. The expression of costimulatory molecules was suppressed even after pretreatment of DCs with LPS or peptidoglycan. Furthermore, the suppressive effects of OmpA⁺ E. coli on DCs were abrogated when the bacteria were incubated with anti-OmpA Ab. The inhibitory effect on DC maturation was associated with increased production of IL-10 as well as TGF-β and decreased production of IL-6, TNF-, IL-1β, and IL-12p70 by DCs, a phenotype associated with tolerogenic DCs. These results suggest that the subversion of DC functions may be a novel strategy deployed by this pathogen to escape immune defense and persist in the infected host to reach a high degree of bacteremia, which is crucial for E. coli to cross the blood-brain barrier.

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 National Institutes of Health Grant AI40567 (to N.V.P.).

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

³ Abbreviations used in this paper: OmpA, outer membrane protein A; DC, dendritic cell; C4bp, C4b-binding protein; PGN, peptidoglycan; MM, maturation mixture; HBMEC, human brain microvascular endothelial cell; PI, propidium iodide; moi, multiplicity of infection; Cm, chloroamphenicol.