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Pathogenesis of Neonatal Meningitis the Maturation of Dendritic Cells In Escherichia coli K1 Promotes the Ligation of CD47 with Thrombospondin-1 To Prevent the Maturation of Dendritic Cells in the Pathogenesis of Neonatal Meningitis This information is current as of October 1, 2021. Rahul Mittal, Ignacio Gonzalez-Gomez and Nemani V. Prasadarao J Immunol 2010; 185:2998-3006; Prepublished online 30 July 2010; doi: 10.4049/jimmunol.1001296 Downloaded from http://www.jimmunol.org/content/185/5/2998 Supplementary http://www.jimmunol.org/content/suppl/2010/07/28/jimmunol.100129 Material 6.DC1 http://www.jimmunol.org/ References This article cites 43 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/185/5/2998.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Escherichia coli K1 Promotes the Ligation of CD47 with Thrombospondin-1 To Prevent the Maturation of Dendritic Cells in the Pathogenesis of Neonatal Meningitis Rahul Mittal,* Ignacio Gonzalez-Gomez,†,‡ and Nemani V. Prasadarao*,‡,x,{ Dendritic cells (DCs) are professional APCs providing a critical link between adaptive and innate immune responses. Our previous studies have shown that Escherichia coli K1 internalization of myeloid DCs suppressed the maturation of the cells for which outer membrane protein A (OmpA) expression is essential. In this study, we demonstrate that infection of DCs with OmpA+ E. coli significantly upregulates the expression of CD47, an integrin-associated protein, and its natural ligand thrombospondin 1 (TSP-1). Pretreatment of DCs with anti-CD47 blocking Ab or knocking down the expression of CD47 or TSP-1, but not signal regulatory protein a by small interfering RNA, abrogated the suppressive effect of E. coli K1. Ligation of CD47 with a mAb prevented the + maturation and cytokine production by DCs upon stimulation with LPS similar to the inhibitory effect induced by OmpA E. coli. Downloaded from In agreement with the in vitro studies, suppression of CD47 or TSP-1 expression in newborn mice by a novel in vivo small interfering RNA technique protected the animals against E. coli K1 meningitis. Reconstitution of CD47 knockdown mice with CD47+ DCs renders the animals susceptible to meningitis by E. coli K1, substantiating the role of CD47 expression in DCs for the occurrence of meningitis. Our results demonstrate a role for CD47 for the first time in bacterial pathogenesis and may be a novel target for designing preventive approaches for E. coli K1 meningitis. The Journal of Immunology, 2010, 185: 2998–3006. http://www.jimmunol.org/ acterial meningitis is the most common and devastating studies have demonstrated that E. coli K1, expressing outer mem- infection of the CNS (1). Escherichia coli K1 is one of the brane protein A (OmpA), enters, survives, and replicates inside most predominant pathogens causing neonatal septicemia myeloid DCs, whereas OmpA2 E. coli was killed within a short B + and meningitis (2). Despite recent advances in antibiotic therapy period (6). Exposure of DCs to live OmpA E. coli K1 prevented and supportive care, bacterial sepsis and meningitis due to E. coli DCs from progressing in their maturation process, as indicated by remain a serious disease with unacceptable rates of mortality and failure to upregulate costimulatory molecules, CD40, HLA-DR, and morbidity (3). The disease is fatal in 5–40% of infected neonates CD86. However, the mechanisms by which E. coli K1 makes DCs and causes neurologic sequelae in up to 30% of the survivors (4). tolerogenic are still not clear. by guest on October 1, 2021 A recent surge in antibiotic-resistant strains of E. coli K1 may The development of fully mature DCs is carefully controlled at increase the mortality rates significantly (5). A comprehensive its multiple differentiation steps, and DCs can be tolerized by understanding of the mechanisms involved at every step of the simultaneous stimulation with endogenous products (7). This pathogenesis is vital to develop new methods of treatment and prevents the detrimental immune response to self and harmless prevention. High degree of bacteremia is a prerequisite for the indigenous flora (8). However, these differentiation control points bacteria to cross the blood-brain barrier, indicating that the bac- can be exploited by pathogens to produce tolerogenic immature terium must evade host defense mechanisms and survive in blood DCs (iDCs) (9). CD47 (integrin-associated protein) is one of or tissues (3). However, precise mechanisms by which E. coli K1 the molecules that have been implicated in the tolerogenicity of survives in host tissues despite the presence of potent immune cells immune cells (10). CD47 is a transmembrane glycoprotein, with like dendritic cells (DCs), neutrophils, macrophages, and T cells are a highly glycosylated extracellular IgG domain at its N terminus, still far from clear. DCs are professional APCs playing a crucial role a hydrophobic five-transmembrane–spanning domain, and a short in the induction and regulation of immune responses. Our previous alternatively spliced cytoplasmic tail (11). It was first identified as a protein associated with vb3 integrins in placenta and in neutrophil granulocytes, and later shown to have the capacity to *Division of Infectious Diseases, xDepartment of Pediatrics, {Department of Surgery, and †Department of Pathology, Saban Research Institute, Children’s Hospital, and regulate integrin function and leukocyte responses to arginine– ‡Keck School of Medicine, University of Southern California, Los Angeles, CA glycine–aspartic acid-containing extracellular matrix proteins (12). 90027 CD47 has also been described to interact with the integrins IIbb3 Received for publication April 20, 2010. Accepted for publication June 28, 2010. and 2b1 (13). Thrombospondin (TSP) is a natural ligand for CD47, This work was supported by National Institutes of Health Grant AI40567 (to N.V.P.). which is a homotrimeric extracellular matrix protein that is produced Address correspondence and reprint requests to Dr. Nemani V. Prasadarao, Division not only by platelets, but also by monocytes, DCs, and macrophages of Infectious Diseases, MS #51, Children’s Hospital Los Angeles and Keck School of (14, 15). Its expression is highly regulated by different hormones Medicine, University of Southern California, 4650 Sunset Boulevard, Los Angeles, CA 90027. E-mail address: [email protected] and cytokines, and is developmentally controlled (16). The levels The online version of this article contains supplemental material. of TSPs in body fluids and their distribution in tissues have been Abbreviations used in this paper: BMDC, bone marrow-derived dendritic cell; DC, correlated with various pathological states (17). TSP-1 is tran- dendritic cell; iDC, immature DC; KD, knockdown; LB, Luria-Bertani; OmpA, outer siently expressed at high concentrations in damaged and inflamed membrane protein A; siRNA, small interfering RNA; SIRP-a, signal regulatory tissues. Signal regulatory protein a (SIRP-a) can also function as protein a; TSP, thrombospondin; WT, wild type. a ligand for CD47 (10, 18). SIRP-a is a type I transmembrane Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 receptor of the Ig superfamily with one or three extracellular Ig www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001296 The Journal of Immunology 2999 domains (alternative splicing) and an intracellular tail with two and/or propidium iodide positive. However, there was no significant differ- ITIMs (19). SIRP-a has been implicated in the suppression of ence observed in the proportion in cultures stimulated with medium, E. coli, anchorage-independent cell growth, mediation of macrophage LPS, or CD47 Ab-treated DCs. multinucleation, skeletal muscle differentiation, neuronal survival, Cytokine determination and synaptogenesis (20, 21). TNF-a, IL-1b, IL-6, IL-12 p70, IL-10, and TGF-b production in cell In this study, we demonstrate for the first time that E. coli K1 culture supernatants of stimulated or unstimulated DCs collected after upregulates the expression of CD47 in DCs, making them tol- 24 and 48 h of incubation were carried out using Biosource (Invitrogen) erogenic so that it can evade immune defense mechanisms and ELISA kits, according to the manufacturer’s instructions. TSP-1 production survive in the host. Furthermore, suppression of CD47 expression was determined using ELISA kit from R&D Systems (Minneapolis, MN). by small interfering RNA (siRNA) in newborn mice protected the DC-induced naive T cell activation animals from E. coli K1-induced meningitis, and adoptive transfer of CD47+ DCs in CD47 knockdown (KD) mice renders them The ability of infected DCs to activate naive T cells was assessed by al- logeneic lymphoproliferation. DCs were infected with E. coli or pretreated susceptible to infection, indicating that CD47 might be a novel with CD47 mAb, CD47 blocking Ab, isotype-matched control Ab, or target for the prevention of this deadly disease. transfected with CD47 siRNA or control siRNA. The DCs were then used to stimulate allogeneic naive T cells. Briefly, DCs and T cells were added in the ratio of 1:300 in 96-well plates, cocultured for 72 h, [3H] was added, Materials and Methods and harvested for 18 h. The rate of incorporation of thymidine was Bacterial strains assessed by a liquid scintillation counter, and the results were expressed as disintegration per minute.
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