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Modulation of Host Signaling Mechanisms by Polysaccharide Immunomodulator as a Novel Therapeutic Approach Against Visceral Leishmaniasis

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Title Modulation of Host Signaling Mechanisms by Polysaccharide Immunomodulator as a Novel Therapeutic Approach Against Visceral Leishmaniasis
 
Creator Sharma, Gunjan
 
Subject Infectious Diseases and Immunology
 
Description Visceral leishmaniasis (VL) or Kala azar is caused by the parasite Leishmania donovani. VL is associated with high fever, splenomegaly and hepatomegaly and if untreated, it can be fatal Current first-line chemotherapy against VL rather depends on a limited number of drugs like pentavalent
antimonial, amphotericin B, and miltefosine, but these drugs have serious problems associated with them as emerging resistance, high toxicity, serious side effects, or high costs. Inactivation of cell-mediated immune system results in parasite-specific clinical symptoms like fever, cachexia, hepatosplenomegaly, anemia and blood cytopenia during VL. Immune response against microbes including, Leishmania is directed via pro-inflammatory and modulatory cytokines. Th1/Th2 paradigm is shifts in favour of Leishmania, and thus parasite survival, during infection resulting in impaired microbicidal machinery of macrophages as evidenced by modification.. IL-12 driven increase in Th1 cells,
macrophage activation, through production of IFN-γ and generation of ROS and NO contributes to the control of L. donovani infection. Th1 cytokine generation and production of ROS is mediated by fucoidan, so we tested its therapeutic
efficacy in both in vitro and in vivo model of visceral leishmaniasis. Our data demonstrated that fucoidan could confer complete protection to both antimonysusceptible
and –resistant L. donovani strains by switching the functional differentiation of Th2-type CD4+ cells to Th1-type as well as up regulation of NO and ROS. NO and ROS generation is a protective strategy of macrophages to clear the Leishmania parasites, which survives within the hostile environment of macrophages by hindering their microbicidal mechanisms of production of ROS and NO. Numerous pathways are intimately involved in strictly regulating the
macrophage effector response and protein kinase C (PKC) signaling pathway is
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one of the most ancient and conserved pathways, which plays an important role in
generation of ROS and NO. Leishmania parasite promotes its survival within the
macrophage by dysregulating PKC pathway. PKC is activated via its membrane
insertion and, lipophosphoglycan (LPG), a leishmanial surface molecule is known
to negatively regulate typical PKC isoforms by inhibiting their membrane
insertion. Leishmania is known to increase the expression of atypical PKC
isoforms (PKC-ε and ζ), while Ca2+ dependent PKC-β expression decreases
during infection. IL-10 production is a characterstic Th2 cytokine which
increases during infection and Leishmania parasite are known to increase IL-10
production via deactivation of PKC-β. Moreover NF-κB, a major transcription
factor known to assist host immune system in clearing the parasite burden is also
dysregulated by Leishmania, via modulation of PKC signaling. MAPK pathway,
which is upstream to NF-κB is also known to be inhibited by Leishmania
parasites for its survival with the host. Activation of MAPK signaling pathways
by various stimuli induced NF-κB activation either through the phosphorylation
of its inhibitor, IκB or by direct post-transcriptional modification of its p65
subunit. Thus, Leishmania successfully evades the macrophage microbicidal
machinery and thrives in, through deregulating production of NO and ROS.
Establishment of an effective immune response therefore may depend on
stimulation of PKC signaling as well as MAPK-mediated activation of NF-κB,
which may prove a potential advancement in therapy of leishmaniasis.
Previously we have already established that fucoidan can completely cure
both antimony-susceptible and-resistant strains of L. donovani through NO and
ROS upregulation. Shifting of Th1/Th2 paradigm in favour of host was the main
effect of fucoidan, which ultimately resulted in increased production of NO and
ROS and clearance of parasetimia. Our present study clearly demonstrated that
antileishmanial response of fucoidan was mediated via induction of iNOS and
pro-inflammatory cytokines as well as activation of p38 and ERK1/2 MAPK,
which in turn activated NF-κB. Interestingly, further investigations illuminated
the functional involvement of distinct PKC isoforms in fucoidan-mediated MAPK
activation. Moreover, the present investigation provides the first in vivo evidence
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for the fact that activation of NF-κB by fucoidan may be a prerequisite for shifting
the cytokine balance toward disease-resolving Th1 mode for complete elimination
of organ parasite burden.
Chapter III
Natural compounds are gaining importance since it has filled the void in
the search of the alternative compounds with anti-parasitic activity. Many dietary
compounds have assessed as potential chemopreventive agents. Fucoidan, a
polyanionic, sulphated polysaccharide mainly consisting of L-fucose, is known to
maintain the cell wall integrity of brown algae, and has many important biological
functions including anti-angiogenic, anti-tumour, antimalarial, contraceptive and
immuno-modulatory activities. Immunomodulatory and antitumor effects of
Fucoidan may be mediated by the release of NO and ROS from macrophages.
Phosphorylation of kinase plays an important role in activation of macrophages,
but uncontrolled activation of anything is harmful which could be detrimental for
the cell. It is necessary for the cells that both the protein kinases and phosphatases
maintain their physiological balance to sustain a normal regulation of events. The
present investigation was aimed towards exploring whether ROS has any effect
on the kinase phosphatase balance maintained by fucoidan mediated
antileishmanial effect in macrophage culture as well as in animal model of
visceral leishmaniasis. Moreover, we found that ROS quencher NAC can revert
the beneficial effects mediated by fucoidan as Th1 cytokine production, activation
of p38 and ERK MAPK.
 
Date 2012
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1839/1/gunjan_thesis.pdf
Sharma, Gunjan (2012) Modulation of Host Signaling Mechanisms by Polysaccharide Immunomodulator as a Novel Therapeutic Approach Against Visceral Leishmaniasis. PhD thesis, Calcutta University.
 
Relation http://www.eprints.iicb.res.in/1839/