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Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality.

Abstract：

:Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome-wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi-based gene knockdown and KO mice, we demonstrated that a strong type I IFN (IFN-I) response triggered by RNA polymerase III and melanoma differentiation-associated protein 5, not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine on infected RBCs might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Wu J,Tian L,Yu X,Pattaradilokrat S,Li J,Wang M,Yu W,Qi Y,Zeituni AE,Nair SC,Crampton SP,Orandle MS,Bolland SM,Qi CF,Long CA,Myers TG,Coligan JE,Wang R,Su XZ

doi

10.1073/pnas.1316467111

subject

Has Abstract

pub_date

2014-01-28 00:00:00

pages

E511-20

issue

eissn

0027-8424

issn

1091-6490

pii

1316467111

journal_volume

111

pub_type

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Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality.