Leishmania Exosomes Modulate Innate and Adaptive Immune Responses through Effects on Monocytes and Dendritic Cells

Abstract

We investigated the properties of leishmania exosomes with respect to influencing innate and adaptive immune responses. Exosomes from Leishmania donovani modulated human monocyte cytokine responses to IFN-γ in a bimodal fashion by promoting IL-10 production and inhibiting that of TNF-α. Moreover, these vesicles were inhibitory with respect to cytokine responses (IL-12p70, TNF-α, and IL-10) by human monocyte-derived dendritic cells. Exosomes from wild-type (WT) L. donovani failed to prime monocyte-derived dendritic cells to drive the differentiation of naive CD4 T cells into IFN-γ–producing Th1 cells. In contrast, vesicles from heat shock protein (HSP)100−/− L. donovani showed a gain-of-function and proinflammatory phenotype and promoted the differentiation of naive CD4 lymphocytes into Th1 cells. Proteomic analysis showed that exosomes from WT and HSP100−/− leishmania had distinct protein cargo, suggesting that packaging of proteins into exosomes is dependent in part on HSP100. Treatment of C57BL/6 mice with WT L. donovani exosomes prior to challenge with WT organisms exacerbated infection and promoted IL-10 production in the spleen. In contrast, HSP100−/− exosomes promoted spleen cell production of IFN-γ and did not adversely affect hepatic parasite burdens. Furthermore, the proparasitic properties of WT exosomes were not species specific because BALB/c mice exposed to Leishmania major exosomes showed increased Th2 polarization and exacerbation of disease in response to infection with L. major. These findings demonstrate that leishmania exosomes are predominantly immunosuppressive. Moreover, to our knowledge, this is the first evidence to suggest that changes in the protein cargo of exosomes may influence the impact of these vesicles on myeloid cell function.

Characterization of exosomes derived from <em>Toxoplasma gondii</em> and their functions in modulating immune responses

“…19 Additionally, parasite-derived exosomes have been shown to promote immune cell activation, and induce cytokine production. 11,13 Silverman et al have investigated the properties of exosomes from Leishmania donovani in terms of affecting innate and adaptive immune responses, resulting in high IFN-γ, high IL-10, and low TNF-α in human monocytes. 11 Twu et al have reported that T. vaginalis exosomes specifically modulate the production of IL-8 rather than IL-6 production in human cervical epithelial cells.…”

“…For instance, Leishmania exosomes could modulate the innate and adaptive immune responses in C57BL/6 mice by affecting monocytes and dendritic cells. 11 In addition, these exosomes could deliver effector cargoes to the target cells during parasite early invasion via the host immunosuppression. 12 Exosomes secreted by T. vaginalis have been found to play important roles in material exchanges and parasite adherence.…”

The languages of parasite communication

“…The definition of excreted molecules was rather vague, essentially encompassing all molecules that did not appear to follow classical secretion pathways. In the past few years, however, several parasites have been shown to produce membrane-bound vesicles that increase their chances of survival and transmission [10][11][12][29][30][31][32][33][34]. In theory, there are many ways in which the contents of these vesicles can be delivered to cells within the host.…”

“…One is the ability to recruit macrophages to the inoculation site; the other is to stimulate the conversion of arginine to polyamines, which are required for growth of Leishmania, rather than nitric oxide, which activates macrophages and promotes parasite killing [49]. Leishmania promastigotes were among the first examples of parasites that were shown to extrude exosomes in culture [31][32][33]. In common with extracellular vesicles from Trichomonas and T. cruzi, these are enriched for specific fragments of tRNAs and rRNAs [33].…”

“…Very recently, it was demonstrated that exosomes with the same composition as culture-derived exosomes are produced by parasites in the sand fly and that these enhance the parasite load when co-injected with parasites [34]. In common with the other organisms described above, exosomes from Leishmania manipulate cytokine secretion, in this case enhancing the production of pro-inflammatory cytokines IL8 and IL17a, while inhibiting the production of TNFα, IL10 and IL12p70 [31,32]. It has also been reported that infection with L. donovani lowers the expression of a microRNA, miR-122, in the liver, resulting in lowered serum cholesterol [50].…”