Given the ability of the malaria parasite to modulate the activity of our immune system, the efficacy of currently developed vaccines is limited. It is in this context that researchers from Inserm are proposing an innovative approach to uncovering new vaccine targets. An approach which involves revealing specifically-presented antigens that are recognized by immune cells.
The Plasmodium parasites responsible for malaria are infectious agents that are difficult to fight. This is reflected by the slow development of immunity in chronically exposed populations and the scale of severe and fatal forms of the disease occurring at a very young age. The parasite has the capability to limit the activity of immune processes that are essential for rapid and efficient antibody production.
The activity of a category of immune system cells, known as CD4 lymphocytes (or CD4 T cells), is found to be particularly disrupted in infected individuals. A dual phenomenon is observed in which, on the one hand, these cells are unable to efficiently contribute to the production of protective antibodies and, on the other, they are too active, locally, in the severe forms (cerebral malaria) where their production of inflammatory cytokines is excessive. However, if we are able to dissociate the two mechanisms and restore the first while limiting the second, this phenomenon is far from being inevitable. This was the objective behind the work of Nicolas Blanchard and his team*, in conjunction with other Inserm** and university hospital teams.
In an animal model, the researchers used a proteomics approach to identify the antigens that the dendritic cells - the sentinels of the immune system - present to the CD4 T cells. As such, they were able to identify those that were for the most part responsible for lymphocyte activation. The researchers also described the subtype of dendritic cell primarily involved in the presentation of these antigenic peptides. "This approach, unprecedented in malaria, offers a better understanding of the immune modulation that occurs during the response to malaria, explains Nicolas Blanchard. This concept, developed in an animal model, must now be transposed to humans by conducting the same analysis using human cells infected with malaria. We hope that this will lead to the identification of new vaccine targets and more effective selection of these targets".
Proof of concept
Proteomics consists of characterizing all the proteins that constitute - for example - a cell. When applied to the study of antigenic peptides presented by the dendritic cells, this set of proteins is called an immunopeptidome.
"The dendritic cells internalize the debris of the parasite, break them down into peptides and express them on their surface to activate the lymphocytes", explains the researcher. In this work, his team collected dendritic cells exposed to red blood cells infected with Plasmodium berghei. After specifically retrieving the antigenic peptides present on their surface, the researchers characterized them using mass spectrometry. "We identified 14 antigens, three of which appear to be responsible for more than 30 % of the CD4 T-cell activation, continues Nicolas Blanchard. We were then able to determine that a subtype of dendritic cells, DC1, is superior to all the other immune cells in ensuring this activation". An important finding given that, until that point, DC1s had above all been known to activate CD8 T-cell dependent immunity.
"We do not claim that the 14 identified antigens are the only ones or the same as those implicated in human malaria caused by Plasmodium falciparum. But immunopeptidome mapping has made it possible to identify the most decisive antigens and antigen-presenting cells in the immune response to infection. This approach may help to identify new vaccine targets". And the stakes are high: even after decades of research, malaria continues to infect some 200 million people worldwide and kill 400,000 each year, the majority of whom are children.
* Inserm unit 1043/CNRS/University of Toulouse, Physiopathology Center of Toulouse-Purpan
** Inserm unit 1104/CNRS/Aix-Marseille University (Center of Immunology Marseille-Luminy), Inserm unit 1019/CNRS/Institut Pasteur Lille/Universities of Lille 1 and 2 (Center for Infection & Immunity of Lille), Inserm unit 1201/CNRS/Institut Pasteur Paris (Biology of host-parasite interactions unit), Inserm unit 1135/UPMC (Center for Immunology and Infectious Diseases)