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Functional Analysis Of the Interferon Gamma Signaling in Leishmania donovani Infection

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

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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/