Abstract
Leishmania devices its survival strategy by suppressing the host’s immune functions. The antigen molecules produced by Leishmania interferes with the host’s cell signaling cascades and consequently changes the protein expression pattern of the antigen-presenting cell (APC). This creates an environment suitable for the switching of the T-cell responses from a healing Th1 response to a non-healing Th2 response that is favorable for the continued survival of the parasite inside the host APC. Using a reconstructed signaling network of the intracellular and intercellular reactions between a Leishmania infected APC and T-cell, we propose a computational model to predict the inhibitory effect of the Leishmania infected APC on the T-cell and to identify the regulators of this Th1-/Th2-switching behavior as observed during Leishmania infection. In this work, we hypothesize that a complete removal of the parasite could only be achieved with a simultaneous up-regulation of the healing Th1 response and stimulation of nitric oxide (NO) production from the APCs, and downregulation of the non-healing Th2 response and thereby propose several unique combinations of protein molecules that could elicit this anti-Leishmania immune response. Our results indicate that TLR3 may play a positive role in eliciting NO synthesis, while TLR2 may be responsible for inhibiting an anti-Leishmania immune response. Also, TLR3 overexpression (in the APC), when combined with SHP2 inhibition (in the T cell), produces an anti-Leishmania response that is better than the conventional IFN-gamma or IL12 treatment. A similar anti-Leishmania response is also obtained in another combination where TLR3 (in APC) is overexpressed, and SHC and MKP (of T cell) are inhibited and activated, respectively. Through our study, we also observe that Leishmania infection may induce an upregulation of IFN-beta production from the APC that may lead to an upregulation of the RAP1 and SOCS3 proteins inside the T cell, the potential inhibitors of MAPK and JAK-STAT signaling pathways, respectively, via the TYK2-mediated pathway. This study not only enhances our knowledge in understanding the Th1/Th2 regulatory switch to promote healing response during leishmaniasis but also helps to identify novel combinations of proteins as potential immunomodulators.Electronic supplementary materialThe online version of this article (doi:10.1186/s13637-015-0032-7) contains supplementary material, which is available to authorized users.
Highlights
Cell-mediated immunity (CMI), responsible for confronting the infections caused due to invasion of intracellular pathogens, primarily involves the interactions of the phagocytic antigen-presenting cells (APCs) and the T-lymphocytes
In order to overcome this short-coming, it is necessary to gain insight into the precise mechanism of the regulation by which the Leishmania antigen molecules takes control of the host cell’s signaling processes. Through this in silico modeling study, we have tried to unravel these regulatory mechanisms by focusing on three important aspects of Leishmania immunobiology—(a) effect of Leishmania infection on the gene expression or the protein activation pattern in APC and microbicidal activities, (b) effect of the infection on the T cell gene/protein expression pattern at the molecular level and their influence in pathway level to identify the molecular routes by which Leishmania inhibits T cell functions, and (c) identification of specific regulators that could act as a regulatory switch to skew the Th1/Th2 dynamics towards the healing Th1 response and simultaneously enhance the nitric oxide (NO) production in order to accelerate the parasite clearance from the host cell
We have been able to capture some of the vital aspects of Leishmania infection and the mechanism through which the interaction of the Leishmania antigen molecules with the APC signaling proteins modulate the microbicidal activity of both the APC and T cell
Summary
Cell-mediated immunity (CMI), responsible for confronting the infections caused due to invasion of intracellular pathogens, primarily involves the interactions of the phagocytic antigen-presenting cells (APCs) and the T-lymphocytes This leads to the activation of a series of intra-cellular and inter-cellular biochemical signaling processes, which culminates into synthesis of certain diffusible effector molecules that includes proteins (mostly the cytokines) and microbicidal molecules (e.g., nitric oxide) helping in the clearance of the disease [1]. Higher pathogen load gives rise to a non-healing response in which an upregulation of the Th2 cytokines (e.g., IL10) is observed, that favors the persistence of the Leishmania During this non-healing response, the production of the protective Th1 cytokines, such as IL12, and the microbicidal molecules, such as nitric oxide is downregulated, creating an immune-suppressed condition suitable for the further progression of the disease [6]
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