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Functional Analysis Of the Interferon Gamma Signaling in Leishmania donovani Infection

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Title Functional Analysis Of the Interferon Gamma
Signaling in Leishmania donovani Infection
 
Creator Sen, Subha
 
Subject Infectious Diseases and Immunology
 
Description Leishmaniasis, a diverse group of diseases, is caused by protozoan parasites belonging to the genus
Leishmania. An estimated 500,000 new cases of Visceral Leishmaniasis (VL) occur globally each year,
and a tenth of these cases are fatal (WHO, 2005). Almost 90% of those affected by the disease exist in
five countries: India (especially Bihar), Bangladesh, Nepal, (northeastern), Brazil, and Sudan (WHO,
2005).Cytokines play a critical role in shaping the host immune response to Leishmania infection and
directing the development of protective and non-protective immunities during infection. Cytokines
exert their biological activities through the activation and translocation of transcription factors into the
nucleus whether they drive the expression of specific cytokine-responsive genes. Signal transducer and
activator of transcription (STATs) are transcription factors which play a critical role in mediating
signaling downstream of cytokine receptors and are important for shaping the host immune response
during Leishmania infection. The critical most signature cytokines associated with the disease VL are
IFNγ and IL-10 dictating the immune phenotype of the infected individual and the selective
manipulation of this immune phenotype by the immune competent host or the virulent parasite
denotes resolution or exacerbation of the disease. The disease is associated with paralysis of several
arms of immune system, which includes macrophage unresponsiveness to most prominent
proinflammatory and effector cytokine of IFNγ. This is also clinically correlated by high parasite
burden of spleen and liver despite having high lesional IFN-γ mRNA level and profuse amount of
serum cytokine which is also supported by experimental leishmaniasis data where high level of T- cell
derived IFNγ have been detected. These reports thus generally converge to infer that during active
visceral leishmaniasis, the uncontrolled parasite replication in infected macrophages is not due to
absence of Th1 cytokine namely IFNγ rather the disease remain unrestrained due to lack of active
killing of the amastigotes by macrophages in response to stimulation by IFNγ. The capacity of LD to
suppress classical activation of macrophages by IFNγ in both the initial establishment and effector
phase of the host immuneresponse has been linked to alterations in key tenets of the IFNγ signaling
cascades and contributes to its success as an intracellular pathogen. Although previous reports have
described the essential steps being impaired in the IFNγ signaling cascade in LD infected macrophages,
it has not been clearly established how the initial most or the immediate early steps of the IFNγ
signaling cascade are controlled/ modulated by the parasites. Thus, the study made in this dissertation
delineates an attempt to understand the mechanistic basis of IFNγ signaling signaling and their effect
on visceral leishmaniasis caused by the protozoal pathogen Leishmania donovani, commonly known as
Kala-azar in India. Besides prominent macrophage unresponsiveness to effector cytokine IFNγ, the
disease leishmaniasis is also marked with gross immunosupression by IL-10. During infection it inhibits
the activity of Th1 cells, NK cells, and macrophages, all of which are required for optimal leishmanial clearance but also contribute to tissue damage. In consequence, IL-10 can both impede pathogen
clearance and ameliorate immunopathology. Macrophages are potent antimicrobial effector cells that
can participate in both proinflammatory (classical) and fibrotic (alternatively activated) response. A
population of "regulatory" macrophages has been identified, at least in vitro, characterized by the
production of IL-10 following Fc receptor ligation by immune complexes or IgG-coated Leishmania
amastigotes. IL-10 is also induced in macrophages in vitro following either CD40 ligation or
modulation of macrophage innate and pattern recognition receptors following exposure to Leishmania
spp, leading to the induction of impaired pathogen control. Importantly, macrophage-derived IL-10 can
inhibit differentiation of neighboring cells into classically activated macrophages, allowing the
macrophage population to be self-regulating. The power of the macrophage IL-10/STAT-3 pathway to
facilitate pathogen survival and, thus, the evolutionary advantage conferred by being able to exploit it, is
clearly illustrated in toxoplasmosis and mycobacterial infection. Whereas soon after its discovery initial
data suggested that IL-10 mainly mediates suppressive functions, more recent data showed stimulatory
properties on certain cell populations also. Overall, the effects of IL-10 seem to be quite complex, and
still considering IL-10 just as immunosuppressive and anti-inflammatory (as was done in the past)
might be oversimplifying. Considering IL-10 as immunoregulatory instead of immunosuppressive
might be more appropriate. Nevertheless, the impact of IL-10 is clearly determined by the timing and
site of its production, and these are both likely to be affected by which cells are making IL-10.
Moreover, because IL-10 production by one cell population can affect the ability of other cells to make
IL-10, there is the potential for IL-10-producing cells to regulate each other. In highly virulent infections
of visceral leishmaniasis, eliciting strong proinflammatory responses, IL-10 production from larger
populations of induced (adaptive) Treg seems to be required to minimize pathology during the
resolution phase of the infection; the ability of Th1 cells to coproduce IL-10 and IFN- may favor
simultaneous pathogen clearance and suppression of downstream pathologies. Irrespective of the source
of IL-10 i.e macrophage, DC or T-cells, its production is of potential benefit to both the host (limiting
pathology) and the pathogen (allowing persistent infection and thereby favoring onward transmission).
However, if the source and thus the timing of IL-10 secretion are inappropriate, i.e., produced too early
during a virulent infection or too late during an avirulent infection, overwhelming infection or severe
tissue damage, respectively, will result. Immunological correlates of vaccine and/or chemotherapeutic
efficacy against visceral leishmaniasis are crucially dependant on the cytokine response elicited by these
interventions, where robust IFN response and diminished IL-10 production are considered as key to
successful therapy. A role for IL-10 and regulatory T cells in parasite persistence was demonstrated,
prompting re-evaluation of this age old paradigm of conventional ways of developing vaccines against
leishmania infections, based mostly on attempt to skew immune responses,to "immunological
environment” predominated by IFNγ production and IL-10 elimination. Instead a targeted approach
of modulating the molecules acting downstream of the IL-10 receptors might represent much better “drugable” approach. As signaling pathways can be pharmacologically manipulated, a better knowledge
of their role and the mechanisms whereby they regulate host immune cell functions and pathogen
growth should permit the development of new therapies to control infectious agents. Concomitantly a
detailed investigation was performed about the nature of cytokine signaling in progressive Leishmania
donovani infection mostly in the quest to resolve the underlying mechanism of IFNγ unresponsiveness
and deviation of macrophage deactivation due to over exuberant IL-10 signaling.
 
Date 2010
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/399/1/Thesis_Subha.pdf
Sen, Subha (2010) Functional Analysis Of the Interferon Gamma Signaling in Leishmania donovani Infection. PhD thesis, Jadavpur University.
 
Relation http://www.eprints.iicb.res.in/399/