Escherichia coli K1 promotes the ligation of CD47 with thrombospondin-1 to prevent the maturation of dendritic cells in the pathogenesis of neonatal meningitis.
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 alpha 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. 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.
Mittal
Rahul
R
Division of Infectious Diseases, Saban Research Institute, Children's Hospital, Los Angeles, CA 90027, USA.
Gonzalez-Gomez
Ignacio
I
Prasadarao
Nemani V
NV
D000818:Animals; D000831:Animals, Newborn; D051928:CD47 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D004927:Escherichia coli Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D016920:Meningitis, Bacterial / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011897:Random Allocation; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
D051928:CD47 Antigen; C497894:CD47 protein, human; D006131:Growth Inhibitors; D008024:Ligands; D034741:RNA, Small Interfering; D019700:Thrombospondin 1