Journal
CELLULAR MICROBIOLOGY
Volume 21, Issue 7, Pages -Publisher
WILEY
DOI: 10.1111/cmi.13021
Keywords
extracellular vesicles; immunosuppression; immune evasion; malaria; T cells
Categories
Funding
- Israel Science Foundation (ISF) [619/16, 119034]
- European Research Council (ERC) [757743]
- Helmut Horten Foundation, Agno, Switzerland
- Institut Pasteur
- Pasteur-Weizmann joint research program
- French Parasitology consortium ParaFrap [ANR-11-LABX0024]
- European Research Council (ERC) [757743] Funding Source: European Research Council (ERC)
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Protozoan pathogens secrete nanosized particles called extracellular vesicles (EVs) to facilitate their survival and chronic infection. Here, we show the inhibition by Plasmodium berghei NK65 blood stage-derived EVs of the proliferative response of CD4(+) T cells in response to antigen presentation. Importantly, these results were confirmed in vivo by the capacity of EVs to diminish the ovalbumin-specific delayed type hypersensitivity response. We identified two proteins associated with EVs, the histamine releasing factor (HRF) and the elongation factor 1 alpha (EF-1 alpha) that were found to have immunosuppressive activities. Interestingly, in contrast to WT parasites, EVs from genetically HRF- and EF-1 alpha-deficient parasites failed to inhibit T cell responses in vitro and in vivo. At the level of T cells, we demonstrated that EVs from WT parasites dephosphorylate key molecules (PLC gamma 1, Akt, and ERK) of the T cell receptor signalling cascade. Remarkably, immunisation with EF-1 alpha alone or in combination with HRF conferred a long-lasting antiparasite protection and immune memory. In conclusion, we identified a new mechanism by which P. berghei-derived EVs exert their immunosuppressive functions by altering T cell responses. The identification of two highly conserved immune suppressive factors offers new conceptual strategies to overcome EV-mediated immune suppression in malaria-infected individuals.
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