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Histamine releasing factor and elongation factor 1 alpha secreted via malaria parasites extracellular vesicles promote immune evasion by inhibiting specific T cell responses
Authors:Claudia Demarta‐Gatsi,Anna Rivkin,Vincenzo Di Bartolo,Roger Peronet,Shuai Ding,Pierre‐Henri Commere,Fran  ois Guillonneau,Jacques Bellalou,S  bastien Brû  l  ,Paula Abou Karam,Sidney R. Cohen,Thibault Lagache,Chris J. Janse,Neta Regev‐Rudzki,Salaheddine M  cheri
Affiliation:Claudia Demarta‐Gatsi,Anna Rivkin,Vincenzo Di Bartolo,Roger Peronet,Shuai Ding,Pierre‐Henri Commere,François Guillonneau,Jacques Bellalou,Sébastien Brûlé,Paula Abou Karam,Sidney R. Cohen,Thibault Lagache,Chris J. Janse,Neta Regev‐Rudzki,Salaheddine Mécheri
Abstract: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 1α (EF‐1α) that were found to have immunosuppressive activities. Interestingly, in contrast to WT parasites, EVs from genetically HRF‐ and EF‐1α‐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 (PLCγ1, Akt, and ERK) of the T cell receptor signalling cascade. Remarkably, immunisation with EF‐1α 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.
Keywords:extracellular vesicles  immunosuppression  immune evasion  malaria  T cells
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