Transcriptomics

Dataset Information

2

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 red blood cells (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 gene knockdown and knockout mice, we demonstrated that a strong IFN-I response triggered by RNA Polymerase III and melanoma differentiation-associated protein 5 (MDA5), 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 (PS) on infected RBC (iRBC) 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. Spleen RNA from mice, 4 days post infection with Plasmodium yoelii (strain N67 or N67C), or mock infection (N). Replicates from 6 individual mice per condition.

ORGANISM(S): Mus musculus  

SUBMITTER: Steve P Crampton   Xin-zhuan Su  Timothy G Myers  Marlene S Orandle  John E Coligan  Weishi Yu  Amir Zeituni  Jian Wu  Jian Li  Chen F Qi  Linjie Tian  Rongfu Wang  Silvia M Bolland  Carole A Long 

PROVIDER: E-GEOD-51329 | ArrayExpress | 2014-01-13

SECONDARY ACCESSION(S): GSE51329PRJNA222408

REPOSITORIES: GEO, ArrayExpress

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