The Trypanosoma brucei gambiense Secretome Impairs Lipopolysaccharide-Induced Maturation, Cytokine Production, and Allostimulatory Capacity of Dendritic Cells

Abstract

bTrypanosoma brucei gambiense, a parasitic protozoan belonging to kinetoplastids, is the main etiological agent of human African trypanosomiasis (HAT), or sleeping sickness. One major characteristic of this disease is the dysregulation of the host immune system. The present study demonstrates that the secretome (excreted-secreted proteins) of T. b. gambiense impairs the lipopolysaccharide (LPS)-induced maturation of murine dendritic cells (DCs). The upregulation of major histocompatibility complex class II, CD40, CD80, and CD86 molecules, as well as the secretion of cytokines such as tumor necrosis factor alpha, interleukin-10 (IL-10), and IL-6, which are normally released at high levels by LPS-stimulated DCs, is significantly reduced when these cells are cultured in the presence of the T. b. gambiense secretome. Moreover, the inhibition of DC maturation results in the loss of their allostimulatory capacity, leading to a dramatic decrease in Th1/Th2 cytokine production by cocultured lymphocytes. These results provide new insights into a novel efficient immunosuppressive mechanism directly involving the alteration of DC function which might be used by T. b. gambiense to interfere with the host immune responses in HAT and promote the infectious process.

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

“…The hallmarks of this effect were an inhibition of the LPS‐induced CD83 and HLA‐DR expression, whereas expression of costimulatory molecules and C‐type lectin receptors was not modified. This contrasts with a previous study which found that trypanosome secretome exerts a suppressive activity on LPS‐stimulated murine DCs by inhibiting both the expression of CD80, CD86, CD40 and MHC class II molecules . These differences could be partly explained by the influence of the specificity of the immune response according to different hosts .…”

“…These differences could be partly explained by the influence of the specificity of the immune response according to different hosts . The resulting cytokine profiles reported by Garzon et al were, however, rather similar to those in our study, with inhibition of cytokines with both inflammatory (TNF‐α) and counter‐inflammatory (IL‐10) properties. This contrasts with some data from clinical settings.…”

“…Antigen‐presenting cells play a central role in the immune response in trypanosomiasis . Pletinckx et al observed that VSG induces partial maturation of murine DCs, leading to a default Th2‐cell response that does not have anti‐trypanosome activity.…”

“…A clear understanding of the different factors involving host characteristics and the intrinsic properties of the parasite, such as its ability to escape the host immune system, is needed . During trypanosomiasis, dendritic cells, (DCs) play a fundamental role in the adaptive immune response due to their ability to sense a wide array of antigens, leading to induction of IL‐12 production and to the promotion of T‐helper cell polarization . An impaired allo‐stimulatory capacity of murine DCs in trypanosomiasis leads to a Th‐cell response that does not exert anti‐trypanosome activity .…”

Dealing with environmental challenges: Mechanisms of adaptation in Trypanosoma cruzi

“…This may represent a rapid way of remodeling the surface upon environmental changes without activating protein degradation pathways [75]. It could also represent a mechanism for signaling and regulation of the interaction between parasites and with the host cells [107, 106]. …”