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Host-Parasite Interaction: Modulation of Signaling Pathways in Macrophage and Leishmania and its Impact on Parasite Infectivity

IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata

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Title Host-Parasite Interaction: Modulation of Signaling Pathways in Macrophage and Leishmania and its Impact on Parasite Infectivity
Creator Biswas, Arunima
Subject Cell Biology & Physiology
Description The life cycle of Leishmania is unique in terms of the extent of physiological, biochemical and structural remodeling that occur during differentiation of procyclic promastigotes to metacyclic promastigotes and metacycilc promastigotes to intracellular amastigotes. This human parasite encounters tremendous oxidative burst during macrophage invasion along with a striking shift of temperature and pH (22°C and pH 7.2 in the insect gut to 37°C and pH 5.5 in the parasitophorous vacuole of macrophages). Though macrophages play indispensable role in producing cytokines and chemokines and also activate other inflammatory cells to combat intracellular parasite infections, parasites like Leishmania can impair these activities by taking advantage of the host antiinflammatory response to avoid self-damage by modulating its own biology and host environment and a subset of parasite persist successfully inside the host finally leading to disease manifestations. Though macrophage biology is well studied, the molecular mechanism by which the parasites circumvent the toxic effects of these reactive oxygen species is not fully understood. Studies showed that some Leishmania molecules implicated in anti-oxidant defense by genes like superoxide dismutase (SOD), peroxidoxin, trypanothione reductase and disruption of these genes or transfection with trans-dominant inactive counterparts render the parasite more susceptible to intracellular killing. The ability of Leishmania parasite to resist oxidative stress seems to be coupled with their transformation and there must be some environmental sensing pathway which would trigger the differentiation. Though in closely related kinetoplastida species Trypanosoma, cAMP has been associated with differentiation, most of the studies regarding cAMP response in Leishmania are confined within cloning and characterization of genes associated with cAMP response and no in-depth study regarding the functional participation of these proteins with cellular differentiation and infectivity of the parasite has been taken care of. In our previous study, cAMP response has been implicated as one of the major environmental sensing machineries associated with stress response in Leishmania (Bhattacharya et al., 2008). The multitudinous functions of cAMP require precise spatial and temporal control of its production, degradation and detection. Though novel proteins have been recently identified that critically modulate cAMP signal in several organisms, not much is known about cAMP signaling in Leishmania. We sought to focus on the molecular mechanisms whereby the Leishmania parasites can subvert host surveillance by activating its own antioxidant machineries by cAMP mediated signaling. We here focus on the control of the production of cAMP by receptor adenylate cyclase and whether the total pyrophosphate pool, which is already known to be an environmental sensor in bacteria could control the intracellular cAMP and sought to discuss the role of different cAMP-dependent phosphodiesterases in modulating the cAMP signaling in the parasite. Lastly, within the scope of this work, an attempt has been made to decipher how cAMP signaling grossly affects the parasite to exploit host machineries like modulation of some important enzymes like arginase and whether we could develop some target to affect such host-parasite interaction to aid parasite killing.
Date 2010
Type Thesis
Format application/pdf
Identifier http://www.eprints.iicb.res.in/379/1/Thesis_Arunima.pdf
Biswas, Arunima (2010) Host-Parasite Interaction: Modulation of Signaling Pathways in Macrophage and Leishmania and its Impact on Parasite Infectivity. PhD thesis, Jadavpur University.
Relation http://www.eprints.iicb.res.in/379/