Abstract
BackgroundHost innate immunity contributes to malaria clinical outcome by providing protective inflammatory cytokines such as interferon-γ, and by shaping the adaptive immune response. Plasmodium falciparum (Pf) is the etiologic agent of the most severe forms of human malaria. Natural Killer (NK) cells are lymphocytes of the innate immune system that are the first effectors to produce interferon-γ in response to Pf. However, the molecular bases of Pf-NK cell recognition events are unknown. Our study focuses on the role of Pf erythrocyte membrane protein 1 (PfEMP1), a major Pf virulence factor. PfEMP1 is expressed on parasitized-erythrocytes and participates to vascular obstruction through the binding to several host receptors. PfEMP1 is also a pivotal target for host antibody response to Pf infection.Methodology/Principal FindingsUsing genetically-engineered parasite mutant strains, a human genetic deficiency, and blocking antibodies, we identified two receptor-ligand pairs involved in two uncoupled events occurring during the sensing of Pf infection by NK cells. First, PfEMP1 interaction with one of its host receptor, chondroitin sulfate A, mediates the cytoadhesion of Pf-infected erythrocytes to human NK cell lines, but is not required for primary NK cell activation. Second, intercellular adhesion molecule-1 (ICAM-1), another host receptor for PfEMP1, is mandatory for NK cell interferon-γ response. In this case, ICAM-1 acts via its engagement with its host ligand, LFA-1, and not with PfEMP1, consistent with the obligatory cross-talk of NK cells with macrophages for their production of interferon-γ.Conclusion/SignificancePfEMP1-independent but ICAM-1/LFA-1-dependent events occurring during NK cell activation by Pf highlight the fundamental role of cellular cooperation during innate immune response to malaria.
Highlights
Plasmodium falciparum (Pf) causes the most severe forms of malaria
Since Pf erythrocyte membrane protein 1 (PfEMP1) is responsible for cytoadhesion of infected erythrocytes (IE) to endothelial cells, we hypothesized that this cell surface parasite protein might play a role in IE detection by Natural Killer (NK) cells
We first evaluated the involvement of chondroitin sulfate A (CSA) in the direct detection of IE by NK cells, using the FCR3-CSA parasite strain that has been selected by panning to adhere to CSA [23]
Summary
Plasmodium falciparum (Pf) causes the most severe forms of malaria. Experimental and natural Pf-infection studies suggest that an early IFN-c production is pivotal to the clinical outcome of the disease [1]. PfEMP1 interaction with one of its host receptor, chondroitin sulfate A, mediates the cytoadhesion of Pf-infected erythrocytes to human NK cell lines, but is not required for primary NK cell activation. Intercellular adhesion molecule-1 (ICAM-1), another host receptor for PfEMP1, is mandatory for NK cell interferon-c response. In this case, ICAM-1 acts via its engagement with its host ligand, LFA-1, and not with PfEMP1, consistent with the obligatory cross-talk of NK cells with macrophages for their production of interferon-c. PfEMP1-independent but ICAM-1/LFA-1-dependent events occurring during NK cell activation by Pf highlight the fundamental role of cellular cooperation during innate immune response to malaria
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