Modeling Immune Response to Leishmania Species Indicates Adenosine As an Important Inhibitor of Th-Cell Activation (original) (raw)
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Cytokine, 2017
Adenosine, an endogenous purine nucleoside is one such extracellular signaling molecule whose role in the regulation of anti-inflammatory cytokines and immune pathogenicity in visceral leishmaniasis is indeterminate. Here, we have evaluated the adenosine in the plasma of 20 visceral leishmaniasis (VL) patients during active disease and after successful treatment. We observed the elevated plasma adenosine during active VL disease (26.73±1.95μM) and the level subsides as the treatment progresses and falls to the normal level after successful treatment (4.32±0.45μM). We demonstrated a direct correlation between changes in the plasma adenosine level and the Th1/Th2 balance in VL patients and it was corroborated with in vitro experiment. Further, we delineated the molecular mechanism involved in the elevation of plasma adenosine during visceral leishmaniasis. Our results reveal that the elevated plasma adenosine level associated with pathogenicity and plays a critical role in skewing imm...
Adenosine and Immune Imbalance in Visceral Leishmaniasis: The Possible Role of Ectonucleotidases
Journal of Tropical Medicine, 2012
Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is responsible for most Leishmania-associated deaths. VL represents a serious public health problem that affects many countries. The immune response in leishmaniasis is very complex and is poorly understood. The Th1 versus Th2 paradigm does not appear to be so clear in visceral leishmaniasis, suggesting that other immunosuppressive or immune-evasion mechanisms contribute to the pathogenesis of VL. It has been demonstrated that generation of adenosine, a potent endogenous immunosuppressant, by extracellular enzymes capable to hydrolyze adenosine trinucleotide (ATP) at the site of infection, can lead to immune impairment and contribute to leishmaniasis progression. In this regard, this paper discusses the unique features in VL immunopathogenesis, including a possible role for ectonucleotidases in leishmaniasis.
Cytokine, 2015
Adenosine, an endogenous purine nucleoside is one such extracellular signalling molecule whose role in regulation of anti-inflammatory cytokines and immune pathogenicity in visceral leishmaniasis is not fully understood. Here, we investigated the relationship between Leishmania donovani infection and expression of A2B receptor on monocytes in VL patients in their pre and post treatment stage. We also investigated the molecular mechanisms influencing the interaction between immunopathogenicity and infection by exposing Leishmania donovani pulsed macrophages to Adenosine. A direct correlation of up-regulated A2B expression on monocytes with increased parasite load was also observed. Our results also suggested that A2B receptor activation is critically required for the stimulatory effect of adenosine on IL-10 production and suppression of nitric oxide release. The stimulatory effect of adenosine on Leishmania donovani induced IL-10 production required ERK1/2 activation and is p-38 MAPK...
Frontiers in immunology, 2017
Adenosine is an endogenously released purine nucleoside that signals through four widely expressed G protein-coupled receptors: A1, A2A, A2B, and A3. Of these, A2AR is recognized as mediating major adenosine anti-inflammatory activity. During cutaneous leishmaniasis, adenosine induces immunosuppression, which promotes the establishment of infection. Herein, we demonstrated that A2AR signaling is exploited by Leishmania infantum parasites, the etiologic agent that causes Visceral Leishmaniasis, to successfully colonize the vertebrate host. A2AR gene-deleted mice exhibited a well-developed cellular reaction with a strong Th1 immune response in the parasitized organs. An intense infiltration of activated neutrophils into the disease-target organs was observed in A2AR(-/-) mice. These cells were characterized by high expression of CXCR2 and CD69 on their cell surfaces and increased cxcl1 expression. Interestingly, this phenotype was mediated by IFN-γ on the basis that a neutralizing ant...
PLoS Computational Biology, 2013
Experimental visceral leishmaniasis, caused by infection of mice with the protozoan parasite Leishmania donovani, is characterized by focal accumulation of inflammatory cells in the liver, forming discrete ''granulomas'' within which the parasite is eventually eliminated. To shed new light on fundamental aspects of granuloma formation and function, we have developed an in silico Petri net model that simulates hepatic granuloma development throughout the course of infection. The model was extensively validated by comparison with data derived from experimental studies in mice, and the model robustness was assessed by a sensitivity analysis. The model recapitulated the progression of disease as seen during experimental infection and also faithfully predicted many of the changes in cellular composition seen within granulomas over time. By conducting in silico experiments, we have identified a previously unappreciated level of inter-granuloma diversity in terms of the development of anti-leishmanial activity. Furthermore, by simulating the impact of IL-10 gene deficiency in a variety of lymphocyte and myeloid cell populations, our data suggest a dominant local regulatory role for IL-10 produced by infected Kupffer cells at the core of the granuloma.
Nitric oxide and cellular immunity in experimental cutaneous leishmaniasis
Clinical and Experimental Dermatology, 2003
We examined the local and systemic production of nitric oxide (NO) and the pattern of cytokine during the course of Leishmania mexicana infection in susceptible BALB ⁄ c and resistant C57BL ⁄ 6 mice. NO derivatives were measured in serum, and the expression of inducible nitric oxide synthase (iNOS), interferon (IFN-c), interleukin (IL-4) and epidermal Langerhans cells (LC) was measured in the lesions by immunohistology. Circulating NO concentrations, iNOS+ cell density, IFN-c+ Th1 cells and CD205+ Langerhans cells were higher in early lesions of resistant C57BL ⁄ 6 mice. In contrast, susceptible BALB ⁄ c mice developed chronic and progressive lesions with a predominance of IL-4+ Th2 cells. In both susceptible and resistant mice, lesion size and lymph node volume followed a similar course. The early local and systemic production of NO in resistant mice may be related with the premature production of IFN-c observed, contributing to the resolution of the lesion.
A Mathematical Model of Immune Response in Cutaneous Leishmaniasis
Journal of Biological Systems, 2007
The TH1/TH2 paradigm has been largely used in the interpretation of several diseases, particularly in leishmaniasis. As far as we know there is no mathematical description of this model related to leishmaniasis. We have extended and modified a previous published set of equations1 in order to adapt it to leishmanial disease particularities. The main modifications were: (1) the analysis of logistic and exponential parasite growth curves, (2) the assumption of the TH2 arm of the immune response having a positive action on parasite growth. The set of three simultaneous differential equations describing the TH1 arm, TH2 arm and parasite growth were analyzed for conditions of existence and stability of the solutions. Stable solutions valid for the logistic and exponential parasite growth models, with its possible clinical correlations, were obtained in the following situations: (1) parasite and TH2 extinction [TH1 cure], (2) parasite extinction and TH1/TH2 co-existence [TH1/TH2 cure], (3)...
Serum nitrite level and adenosine deaminase activity is altered in visceral leishmaniasis
Nepal Medical College journal : NMCJ, 2007
In this study we sought to determine if there is alteration in nitric oxide (NO) production and adenosine deaminase (ADA) activity among patients with visceral leishmaniasis (VL) and the effect of four weeks of chemotherapy on these levels. Fifty-three VL patients diagnosed clinically and by direct demonstration of the LD bodies in the bone marrow smear were studied. They were treated with Sodium Stibogluconate and sampled at the baseline and four weeks. Forty-three healthy individuals coming from the same endemic area were taken as control. Total nitrite (NO2- and NO3-) as an index of NO production and ADA activity was measured spectrophotometrically. Serum nitrite level decreased significantly in patients as compared to the healthy individuals but significantly increased following 4 weeks of chemotherapy. Conversely, Increased ADA activity was observed in the beginning of treatment and decreased significantly with successive 4 weeks of chemotherapy. It seems a negative correlation...
Modeling of leishmaniasis infection dynamics: novel application to the design of effective therapies
BMC systems biology, 2012
Background: The WHO considers leishmaniasis as one of the six most important tropical diseases worldwide. It is caused by parasites of the genus Leishmania that are passed on to humans and animals by the phlebotomine sandfly. Despite all of the research, there is still a lack of understanding on the metabolism of the parasite and the progression of the disease. In this study, a mathematical model of disease progression was developed based on experimental data of clinical symptoms, immunological responses, and parasite load for Leishmania amazonensis in BALB/c mice. Results: Four biologically significant variables were chosen to develop a differential equation model based on the GMA power-law formalism. Parameters were determined to minimize error in the model dynamics and time series experimental data. Subsequently, the model robustness was tested and the model predictions were verified by comparing them with experimental observations made in different experimental conditions. The model obtained helps to quantify relationships between the selected variables, leads to a better understanding of disease progression, and aids in the identification of crucial points for introducing therapeutic methods. Conclusions: Our model can be used to identify the biological factors that must be changed to minimize parasite load in the host body, and contributes to the design of effective therapies.