title: Identification of Th1/Th2 regulatory switch to promote healing response during leishmaniasis: a computational approach.
abstract: Leishmaniadevices its survival strategy by suppressing the host's immune functions. The antigen molecules produced byLeishmaniainterferes 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 aLeishmaniainfected APC and T-cell, we propose a computational model to predict the inhibitory effect of theLeishmaniainfected APC on the T-cell and to identify the regulators of this Th1-/Th2-switching behavior as observed duringLeishmaniainfection. 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-Leishmaniaimmune response. Our results indicate that TLR3 may play a positive role in eliciting NO synthesis, while TLR2 may be responsible for inhibiting an anti-Leishmaniaimmune response. Also, TLR3 overexpression (in the APC), when combined with SHP2 inhibition (in the T cell), produces an anti-Leishmaniaresponse that is better than the conventional IFN-gamma or IL12 treatment. A similar anti-Leishmaniaresponse 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 thatLeishmaniainfection 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.
authors.affiliation: Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pune, Maharashtra 411008 India.
authors.forename: Piyali
authors.initials: P
authors.lastname: Ganguli
authors.affiliation: Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pune, Maharashtra 411008 India ; Academy of Scientific & Innovative Research (AcSIR), CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Saikat
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pune, Maharashtra 411008 India.
authors.forename: Shomeek
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pune, Maharashtra 411008 India ; Academy of Scientific & Innovative Research (AcSIR), CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Ram Rup
authors.initials: RR
authors.lastname: Sarkar
keywords: Combinatorial drug targets; Immunotherapy; Leishmania; Logical model; NO synthesis; T cell and APC signaling pathways; Th1/Th2 response