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An In vitro Co-infection Model to Study Plasmodium falciparum-HIV-1 Interactions in Human Primary Monocyte-derived Immune Cells
Published on: August 15, 2012
Parasite-derived plasma microparticles contribute significantly to malaria infection-induced inflammation through
Kevin N Couper1, Tom Barnes, Julius C R Hafalla
1Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Abstract:
There is considerable debate as to the nature of the primary parasite-derived moieties that activate innate pro-inflammatory responses during malaria infection. Microparticles (MPs), which are produced by numerous cell types following vesiculation of the cellular membrane as a consequence of cell death or immune-activation, exert strong pro-inflammatory activity in other disease states. Here we demonstrate that MPs, derived from the plasma of malaria infected mice, but not naive mice, induce potent activation of macrophages in vitro as measured by CD40 up-regulation and TNF production. In vitro, these MPs induced significantly higher levels of macrophage activation than intact infected red blood cells. Immunofluorescence staining revealed that MPs contained significant amounts of parasite material indicating that they are derived primarily from infected red blood cells rather than platelets or endothelial cells. MP driven macrophage activation was completely abolished in the absence of MyD88 and TLR-4 signalling. Similar levels of immunogenic MPs were produced in WT and in TNF(-/-), IFN-gamma(-/-), IL-12(-/-) and RAG-1(-/-) malaria-infected mice, but were not produced in mice injected with LPS, showing that inflammation is not required for the production of MPs during malaria infection. This study therefore establishes parasitized red blood cell-derived MPs as a major inducer of systemic inflammation during malaria infection, raising important questions about their role in severe disease and in the generation of adaptive immune responses.
Insights
Malaria infection releases microparticles (MPs) from red blood cells that strongly activate immune cells. These parasite-derived MPs are a key driver of inflammation during malaria.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- The specific parasite components triggering innate immune responses in malaria remain debated.
- Microparticles (MPs), released from cell membranes, are known pro-inflammatory agents in other conditions.
Purpose of the Study:
- To investigate the role of microparticles (MPs) derived from malaria-infected red blood cells in activating innate immune responses.
- To determine the cellular origin and signaling pathways involved in MP-mediated inflammation during malaria.
Main Methods:
- Analysis of MPs isolated from plasma of malaria-infected and naive mice.
- In vitro assessment of macrophage activation (CD40, TNF) by MPs.
- Immunofluorescence staining to identify MP origin.
- Evaluation of MP production in mice with genetic deficiencies in inflammatory signaling pathways (MyD88, TLR-4, TNF, IFN-gamma, IL-12, RAG-1).
Main Results:
- MPs from malaria-infected mice potently activated macrophages in vitro, exceeding the activation by intact infected red blood cells.
- Immunofluorescence confirmed MPs primarily originate from parasite-infected red blood cells.
- MP-induced macrophage activation was dependent on MyD88 and Toll-like receptor 4 (TLR-4) signaling.
- Immunogenic MP production during malaria infection was independent of TNF, IFN-gamma, IL-12, and RAG-1, and did not require prior LPS exposure.
Conclusions:
- Parasitized red blood cell-derived MPs are significant inducers of systemic inflammation during malaria.
- These MPs activate macrophages via MyD88 and TLR-4 pathways.
- The findings suggest a crucial role for MPs in malaria pathogenesis and adaptive immune responses.
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