Trypanosoma brucei gambiense excreted/secreted factors impair lipopolysaccharide‐induced maturation and activation of human monocyte‐derived dendritic cells

Abstract

Trypanosoma brucei gambiense, an extracellular eukaryotic flagellate parasite, is the main etiological agent of human African trypanosomiasis (HAT) or sleeping sickness. Dendritic cells (DCs) play a pivotal role at the interface between innate and adaptive immune response and are implicated during HAT. In this study, we investigated the effects of T gambiense and its excreted/secreted factors (ESF) on the phenotype of human monocyte‐derived DCs (Mo‐DCs). Mo‐DCs were cultured with trypanosomes, lipopolysaccharide (LPS), ESF derived from T gambiense bloodstream strain Biyamina (MHOM/SD/82), or both ESF and LPS. Importantly, ESF reduced the expression of the maturation markers HLA‐DR and CD83, as well as the secretion of IL‐12, TNF‐alpha and IL‐10, in LPS‐stimulated Mo‐DCs. During mixed‐leucocyte reactions, LPS‐ plus ESF‐exposed DCs induced a non‐significant decrease in the IFN‐gamma/IL‐10 ratio of CD4 + T‐cell cytokines. Based on the results presented here, we raise the hypothesis that T gambiense has developed an immune escape strategy through the secretion of paracrine mediators in order to limit maturation and activation of human DCs. The identification of the factor(s) in the T gambiense ESF and of the DCs signalling pathway(s) involved may be important in the development of new therapeutic targets.

To the Skin and Beyond: The Immune Response to African Trypanosomes as They Enter and Exit the Vertebrate Host

“…From the perspective of host-pathogen interactions, it is clear that trypanosomes release a myriad of virulence factors, including soluble products and extracellular vesicles, thought to be critical to modulate the immune response against them (224)(225)(226)(227)(228). In this case, it would be important to understand whether the secretion of virulence factors differs between metacyclic and long slender trypomastigotes and to what extent these secreted molecules aid in the establishment of chronic infections in the skin.…”

The Trypanosoma brucei-Derived Ketoacids, Indole Pyruvate and Hydroxyphenylpyruvate, Induce HO-1 Expression and Suppress Inflammatory Responses in Human Dendritic Cells

“…The production of large amounts of immunomodulatory aromatic ketoacids during T. brucei infection likely serves to benefit the parasite by prolonging infection, proliferation, and, ultimately, survival in the host. While the secretome of T. brucei has been shown to reduce the secretion of IL-12, IL-10, IL-6, and TNF in both murine and human DC [ 26 , 27 ], the ketoacids, IP and HPP, have been shown to directly ameliorate inflammatory cytokine production in murine macrophages and glia [ 4 , 5 ]. This is further supported by studies demonstrating their therapeutic efficacy in murine models of disease [ 4 , 6 , 7 ].…”