Dataset Information

Monocyte-Derived CD11c+ Cells Acquire Plasmodium from Hepatocytes to Prime CD8 T Cell Immunity to Liver-Stage Malaria.

ABSTRACT: Plasmodium sporozoites inoculated by mosquitoes migrate to the liver and infect hepatocytes prior to release of merozoites that initiate symptomatic blood-stage malaria. Plasmodium parasites are thought to be restricted to hepatocytes throughout this obligate liver stage of development, and how liver-stage-expressed antigens prime productive CD8 T cell responses remains unknown. We found that a subset of liver-infiltrating monocyte-derived CD11c+ cells co-expressing F4/80, CD103, CD207, and CSF1R acquired parasites during the liver stage of malaria, but only after initial hepatocyte infection. These CD11c+ cells found in the infected liver and liver-draining lymph nodes exhibited transcriptionally and phenotypically enhanced antigen-presentation functions and primed protective CD8 T cell responses against Plasmodium liver-stage-restricted antigens. Our findings highlight a previously unrecognized aspect of Plasmodium biology and uncover the fundamental mechanism by which CD8 T cell responses are primed against liver-stage malaria antigens.

SUBMITTER: Kurup SP

PROVIDER: S-EPMC6459714 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Monocyte-Derived CD11c<sup>+</sup> Cells Acquire Plasmodium from Hepatocytes to Prime CD8 T Cell Immunity to Liver-Stage Malaria.

Kurup Samarchith P SP Anthony Scott M SM Hancox Lisa S LS Vijay Rahul R Pewe Lecia L LL Moioffer Steven J SJ Sompallae Ramakrishna R Janse Chris J CJ Khan Shahid M SM Harty John T JT

Cell host & microbe 20190321 4

Plasmodium sporozoites inoculated by mosquitoes migrate to the liver and infect hepatocytes prior to release of merozoites that initiate symptomatic blood-stage malaria. Plasmodium parasites are thought to be restricted to hepatocytes throughout this obligate liver stage of development, and how liver-stage-expressed antigens prime productive CD8 T cell responses remains unknown. We found that a subset of liver-infiltrating monocyte-derived CD11c<sup>+</sup> cells co-expressing F4/80, CD103, CD20 ...[more]

PMID: 30905437

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Project description:BackgroundFifteen volunteers were immunized with three doses of plasmid DNA encoding P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1) and boosted with human adenovirus-5 (Ad) expressing the same antigens (DNA/Ad). Four volunteers (27%) demonstrated sterile immunity to controlled human malaria infection and, overall, protection was statistically significantly associated with ELISpot and CD8+ T cell IFN-? activities to AMA1 but not CSP. DNA priming was required for protection, as 18 additional subjects immunized with Ad alone (AdCA) did not develop sterile protection.Methodology/principal findingsWe sought to identify correlates of protection, recognizing that DNA-priming may induce different responses than AdCA alone. Among protected volunteers, two and three had higher ELISpot and CD8+ T cell IFN-? responses to CSP and AMA1, respectively, than non-protected volunteers. Unexpectedly, non-protected volunteers in the AdCA trial showed ELISpot and CD8+ T cell IFN-? responses to AMA1 equal to or higher than the protected volunteers. T cell functionality assessed by intracellular cytokine staining for IFN-?, TNF-? and IL-2 likewise did not distinguish protected from non-protected volunteers across both trials. However, three of the four protected volunteers showed higher effector to central memory CD8+ T cell ratios to AMA1, and one of these to CSP, than non-protected volunteers for both antigens. These responses were focused on discrete regions of CSP and AMA1. Class I epitopes restricted by A*03 or B*58 supertypes within these regions of AMA1 strongly recalled responses in three of four protected volunteers. We hypothesize that vaccine-induced effector memory CD8+ T cells recognizing a single class I epitope can confer sterile immunity to P. falciparum in humans.Conclusions/significanceWe suggest that better understanding of which epitopes within malaria antigens can confer sterile immunity and design of vaccine approaches that elicit responses to these epitopes will increase the potency of next generation gene-based vaccines.

Dataset Information

Monocyte-Derived CD11c+ Cells Acquire Plasmodium from Hepatocytes to Prime CD8 T Cell Immunity to Liver-Stage Malaria.

Publications

Monocyte-Derived CD11c<sup>+</sup> Cells Acquire Plasmodium from Hepatocytes to Prime CD8 T Cell Immunity to Liver-Stage Malaria.

Similar Datasets

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