Histamine releasing factor and elongation factor 1 alpha secreted via malaria parasites extracellular vesicles promote immune evasion by inhibiting specific T cell responses

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.

miR-21 Expression Determines the Early Vaccine Immunity Induced by LdCen−/− Immunization

“…Recent studies showed that intracellular parasites utilize exosome mediated signaling with the host immune cells to alter host immunity (25–27) Further, in the early time points after infection, we observed that miR-21 levels were altered in bystander cells (RFP/mCherry negative population) in addition to the parasitized cells (RFP/mCherry positive population, Figures 2B–D). Consistent with this observation, at 12 h post infection, IL-12 levels were also significantly higher in LdCen −/−mCherry parasitized cells compared to LdWT RFP infection.…”

Evaluation on Elongation Factor 1 Alpha of Entamoeba histolytica Interaction with the Intermediate Subunit of the Gal/GalNAc Lectin and Actin in Phagocytosis

“…EF1a is also found in extracellular vehicles (EVs) of Plasmodium berghei. EF1a in combination with another EVs factor, termed histamine releasing factor (HRF), inhibits antigen-specific T cell responses through interference with key phosphorylation pathways associated with T cell receptor (TCR) signaling [12]. This action facilitates parasite escape from host immune responses.…”

“…There are an interesting fact that the 12 amino acid deletions in EF1a have been found in some pathogenic protozoans of major global health importance, including Leishmania donovani [10,11], Plasmodia spp. [12], Giardia lamblia [13], Toxoplasma gondii [14], Cryptosporidium parvum [15,16], Trypanosoma cruzi [17], T. brucei brucei, and Entamoeba histolytica [10,18]. The same amino acid sequence deletion compared with human EF1a, indicated targeting the exposed region of EF1a common to all of these pathogens could have far-reaching benefits.…”

XPO1E571K Mutation Modifies Exportin 1 Localisation and Interactome in B-Cell Lymphoma

“…Nano-liquid chromatography and MS analyses were performed on a 2 h run per replicate as previously described [ 46 ]. The mass spectrometry experimental data were compared with theoretical data using Mascot v2.5.1 (Matrix science) on a Homo sapiens (23,076 sequences) SwissProt protein database (October 2018) and an in-house database containing the E571K sequence variant of XPO1.…”