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Title: Malaria Blood Stage Parasites Activate Human Plasmacytoid Dendritic Cells and Murine Dendritic Cells through a Toll-Like Receptor 9-Dependent Pathway
Authors: Sathit Pichyangkul
Kosol Yongvanitchit
Utaiwan Kum-Arb
Hiroaki Hemmi
Shizuo Akira
Arthur M. Krieg
D. Gray Heppner
V. Ann Stewart
Hitoshi Hasegawa
Sornchai Looareesuwan
G. Dennis Shanks
R. Scott Miller
Armed Forces Research Institute of Medical Sciences, Thailand
Osaka University
Pfizer Inc.
Walter Reed Army Institute of Research
Ehime University, School of Medicine
Mahidol University
Keywords: Immunology and Microbiology
Issue Date: 15-Apr-2004
Citation: Journal of Immunology. Vol.172, No.8 (2004), 4926-4933
Abstract: A common feature of severe Plasmodium falciparum infection is the increased systemic release of proinflammatory cytokines that contributes to the pathogenesis of malaria. Using human blood, we found that blood stage schizonts or soluble schizont extracts activated plasmacytoid dendritic cells (PDCs) to up-regulate CD86 expression and produce IFN-α. IFN-α production was also detected in malaria-infected patients, but the levels of circulating PDCs were markedly reduced, possibly because of schizont-stimulated up-regulation of CCR7, which is critical for PDC migration. The schizont-stimulated PDCs elicited a poor T cell response, but promoted γδ T cell proliferation and IFN-γ production. The schizont immune stimulatory effects could be reproduced using murine DCs and required the Toll-like receptor 9 (TLR9)-MyD88 signaling pathway. Although the only known TLR9 ligand is CpG motifs in pathogen DNA, the activity of the soluble schizont extract was far greater than that of schizont DNA, and it was heat labile and precipitable with ammonium sulfate, unlike the activity of bacterial DNA. These results demonstrate that schizont extracts contain a novel and previously unknown ligand for TLR9 and suggest that the stimulatory effects of this ligand on PDCs may play a key role in immunoregulation and immunopathogenesis of human falciparum malaria.
ISSN: 00221767
Appears in Collections:Scopus 2001-2005

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