scholarly journals Mononuclear Cell Recruitment, Granuloma Assembly, and Response to Treatment in Experimental Visceral Leishmaniasis: Intracellular Adhesion Molecule 1-Dependent and -Independent Regulation

2000 ◽  
Vol 68 (11) ◽  
pp. 6294-6299 ◽  
Author(s):  
Henry W. Murray
Keyword(s):  
Visceral Leishmaniasis ◽  
Mononuclear Cell ◽  
Leishmania Donovani ◽  
Acquired Resistance ◽  
Tissue Response ◽  
Response To Treatment ◽  
Th1 Cell ◽  
Intracellular Adhesion Molecule ◽  
Granulomatous Tissue ◽  
High Level

ABSTRACT In experimental visceral leishmaniasis, acquired resistance to intracellular Leishmania donovani is Th1 cell cytokine dependent and largely mediated by gamma interferon (IFN-γ); the same response also permits conventional antimony (Sb) chemotherapy to express its leishmanicidal effect. Since the influxing blood monocyte (which utilizes endothelial cell ICAM-1 for adhesion and tissue entry) is a primary effector target cell for this cytokine mechanism, we tested the monocyte's role in host responsiveness to chemotherapy in mice with ICAM-1 gene disruptions. Mutant animals failed to develop any early granulomatous tissue response in the liver, initially supported high-level visceral parasite replication, and showed no killing after Sb treatment; the leishmanicidal response to a directly acting, alternative chemotherapeutic probe, amphotericin B, was intact. However, mutant mice proceeded to express a compensatory, ICAM-1-independent response leading to mononuclear cell influx and granuloma assembly, control over visceral infection, and the capacity to respond to Sb. Together, these results point to the recruitment of emigrant monocytes and mononuclear cell granuloma formation, mediated by ICAM-1-dependent and -independent pathways, as critical determinants of host responsiveness to conventional antileishmanial chemotherapy.

scholarly journals Interleukin-10 (IL-10) in Experimental Visceral Leishmaniasis and IL-10 Receptor Blockade as Immunotherapy

2002 ◽  
Vol 70 (11) ◽  
pp. 6284-6293 ◽  
Author(s):  
Henry W. Murray ◽  
Christina M. Lu ◽  
Smita Mauze ◽  
Sherry Freeman ◽  
Andre L. Moreira ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Transgenic Mice ◽  
Leishmania Donovani ◽  
Interleukin 10 ◽  
Th1 Cell ◽  
Th1 Cytokine ◽  
Parasite Replication ◽  
High Level ◽  
Oxide Synthase ◽  
Established Infection

ABSTRACT Interleukin-10 (IL-10) is thought to promote intracellular infection, including human visceral leishmaniasis, by disabling Th1 cell-type responses and/or deactivating parasitized tissue macrophages. To develop a rationale for IL-10 inhibition as treatment in visceral infection, Th1 cytokine-driven responses were characterized in Leishmania donovani-infected BALB/c mice in which IL-10 was absent or overexpressed or its receptor (IL-10R) was blockaded. IL-10 knockout and normal mice treated prophylactically with anti-IL-10R demonstrated accelerated granuloma assembly and rapid parasite killing without untoward tissue inflammation; IL-12 and gamma interferon mRNA expression, inducible nitric oxide synthase reactivity, and responsiveness to antimony chemotherapy were also enhanced in knockout mice. In IL-10 transgenic mice, parasite replication was unrestrained, and except for antimony responsiveness, measured Th1 cell-dependent events were all initially impaired. Despite subsequent granuloma assembly, high-level infection persisted, and antimony-treated transgenic mice also relapsed. In normal mice with established infection, anti-IL-10R treatment was remarkably active, inducing near-cure by itself and synergism with antimony. IL-10's deactivating effects regulate outcome in experimental visceral leishmaniasis, and IL-10R blockade represents a potential immuno- and/or immunochemotherapeutic approach in this infection.

scholarly journals Modulation of T-Cell Costimulation as Immunotherapy or Immunochemotherapy in Experimental Visceral Leishmaniasis

2003 ◽  
Vol 71 (11) ◽  
pp. 6453-6462 ◽  
Author(s):  
Henry W. Murray ◽  
Cristina M. Lu ◽  
Elaine B. Brooks ◽  
Richard E. Fichtl ◽  
Jennifer L. DeVecchio ◽  
...  
Keyword(s):  
T Cell ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Cytotoxic T Lymphocyte ◽  
Acquired Resistance ◽  
Cd40 Ligand ◽  
Response To Treatment ◽  
Interleukin 12 ◽  
Ifn Γ ◽  
Visceral Infection

ABSTRACT CD40 ligand (CD40L)-deficient C57BL/6 mice failed to control intracellular Leishmania donovani visceral infection, indicating that acquired resistance involves CD40-CD40L signaling and costimulation. Conversely, in wild-type C57BL/6 and BALB/c mice with established visceral infection, injection of agonist anti-CD40 monoclonal antibody (MAb) induced killing of ∼60% of parasites within liver macrophages, stimulated gamma interferon (IFN-γ) secretion, and enhanced mononuclear cell recruitment and tissue granuloma formation. Comparable parasite killing was also induced by MAb blockade (inhibition) of cytotoxic T lymphocyte antigen-4 (CTLA-4) which downregulates separate CD28-B7 T-cell costimulation. Optimal killing triggered by both anti-CD40 and anti-CTLA-4 required endogenous IFN-γ and involved interleukin 12. CD40L−/− mice also failed to respond to antileishmanial chemotherapy (antimony), while in normal animals, anti-CD40 and anti-CTLA-4 synergistically enhanced antimony-associated killing. CD40L-CD40 signaling regulates outcome and response to treatment of experimental visceral leishmaniasis, and MAb targeting of T-cell costimulatory pathways (CD40L-CD40 and CD28-B7) yields macrophage activation and immunotherapeutic and immunochemotherapeutic activity.

scholarly journals Granzyme-Mediated Regulation of Host Defense in the Liver in Experimental Leishmania donovani Infection

2014 ◽  
Vol 83 (2) ◽  
pp. 702-712 ◽  
Author(s):  
Henry W. Murray ◽  
Marisa Mitchell-Flack ◽  
Hua Zheng ◽  
Xiaojing Ma
Keyword(s):  
Host Defense ◽  
Leishmania Donovani ◽  
Early Stage ◽  
Acquired Resistance ◽  
Double Knockout ◽  
Th1 Cell ◽  
Content Type ◽  
Infected Liver ◽  
Parasite Replication ◽  
Cell Effector Function

In the livers of susceptible C57BL/6 (B6) mice infected withLeishmania donovani, CD8+T cell mechanisms are required for granuloma assembly, macrophage activation, intracellular parasite killing, and self-cure. Since gene expression of perforin and granzymes A and B (GzmA and GzmB), cytolytic proteins linked to CD8+cell effector function, was enhanced in infected liver tissue, B6 mice deficient in these granular proteins were used to gauge host defense roles. Neither perforin nor GzmA was required; however, mice deficient in GzmB (GzmB−/−, GzmB cluster−/−, and GzmA×B cluster double knockout [DKO] mice) showed both delayed granuloma assembly and initially impaired control of parasite replication. Since these two defects in B6 mice were limited to early-stage infection, innately resistant 129/Sv mice were also tested. In this genetic setting, expression of both innate and subsequent T (Th1) cell-dependent acquired resistance, including the self-cure phenotype, was entirely derailed in GzmA×B cluster DKO mice. These results, in susceptible B6 mice for GzmB and in resistant 129/Sv mice for GzmA and/or the GzmB cluster, point to granzyme-mediated host defense regulation in the liver in experimental visceral leishmaniasis.

scholarly journals Immunoenhancement Combined with Amphotericin B as Treatment for Experimental Visceral Leishmaniasis

2003 ◽  
Vol 47 (8) ◽  
pp. 2513-2517 ◽  
Author(s):  
Henry W. Murray ◽  
Elaine B. Brooks ◽  
Jennifer L. DeVecchio ◽  
Frederick P. Heinzel
Keyword(s):  
Visceral Leishmaniasis ◽  
Total Dose ◽  
Amphotericin B ◽  
Leishmania Donovani ◽  
Low Dose ◽  
Interleukin 12 ◽  
Th1 Cell ◽  
Killing Effect ◽  
Ifn Γ ◽  
Visceral Infection

ABSTRACT To determine if stimulation of Th1-cell-associated immune responses, mediated by interleukin 12 (IL-12) and gamma interferon (IFN-γ), enhance the antileishmanial effect of amphotericin B (AMB), Leishmania donovani-infected BALB/c mice were first treated with (i) exogenous IL-12 to induce IFN-γ, (ii) agonist anti-CD40 monoclonal antibody (MAb) to maintain IL-12 and induce IFN-γ, or (iii) anti-IL-10 receptor (IL-10R) MAb to blockade suppression of IL-12 and IFN-γ. In animals with established visceral infection, low-dose AMB alone (two injections of 1 mg/kg of body weight; total dose, 2 mg/kg) killed 15 to 29% of liver parasites; by themselves, the immunointerventions induced 16 to 33% killing. When the interventions were combined, the leishmanicidal activities increased 3.4-fold (anti-CD40), 6.3-fold (anti-IL-10R), and 9-fold (IL-12) compared with the activities of AMB plus the control preparations; and overall killing (76 to 84%) approximated the 84 to 92% killing effect of 7.5-fold more AMB alone (three injections of 5 mg/kg; total dose, 15 mg/kg). These results suggest that strengthening the host Th1-cell response may be a strategy for the development of AMB-sparing regimens in visceral leishmaniasis.

scholarly journals Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

2019 ◽  
Vol 3 ◽  
pp. 135 ◽  
Author(s):  
Helen Ashwin ◽  
Karin Seifert ◽  
Sarah Forrester ◽  
Najmeeyah Brown ◽  
Sandy MacDonald ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Peripheral Blood ◽  
Leishmania Donovani ◽  
Systemic Disease ◽  
Tissue Response ◽  
New Drugs ◽  
Immune Checkpoints ◽  
Tissue Specific ◽  
Transcriptomic Data ◽  
Human Visceral Leishmaniasis

Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease.  Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.

scholarly journals Real-time PCR in detection and quantitation of Leishmania donovani for the diagnosis of Visceral Leishmaniasis patients and the monitoring of their response to treatment

PLoS ONE ◽  
2017 ◽  
Vol 12 (9) ◽  
pp. e0185606 ◽  
Author(s):  
Faria Hossain ◽  
Prakash Ghosh ◽  
Md. Anik Ashfaq Khan ◽  
Malcolm S. Duthie ◽  
Aarthy C. Vallur ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Real Time ◽  
Real Time Pcr ◽  
Leishmania Donovani ◽  
Response To Treatment

scholarly journals Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

2018 ◽  
Vol 3 ◽  
pp. 135 ◽  
Author(s):  
Helen Ashwin ◽  
Karin Seifert ◽  
Sarah Forrester ◽  
Najmeeyah Brown ◽  
Sandy MacDonald ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Peripheral Blood ◽  
Leishmania Donovani ◽  
Systemic Disease ◽  
Tissue Response ◽  
New Drugs ◽  
Immune Checkpoints ◽  
Tissue Specific ◽  
Transcriptomic Data ◽  
Human Visceral Leishmaniasis

Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease.  Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.

scholarly journals Accelerated Control of Visceral Leishmania donovani Infection in Interleukin-6-Deficient Mice

2008 ◽  
Vol 76 (9) ◽  
pp. 4088-4091 ◽  
Author(s):  
Henry W. Murray
Keyword(s):  
Visceral Leishmaniasis ◽  
Interleukin 6 ◽  
Leishmania Donovani ◽  
Wild Type ◽  
Therapeutic Blockade ◽  
Th1 Cell ◽  
Kala Azar ◽  
Type Response ◽  
Deficient Mice

ABSTRACT In patients with visceral leishmaniasis, increased levels of circulating interleukin-6 (IL-6) regularly accompany fully expressed, progressive infections (kala-azar). To experimentally test the role of IL-6, responses to an intracellular Leishmania donovani infection in the livers of IL-6−/− and wild-type mice were compared. IL-6−/− mice showed an enhanced control of the infection and earlier, rapid parasite killing along with additional evidence of a stimulated antileishmanial Th1-cell-type response: increased levels of circulating gamma interferon, accelerated granuloma assembly, and heightened responsiveness to chemotherapy. In this model of visceral leishmaniasis, IL-6 appears to act in a suppressive, macrophage-deactivating fashion, which identifies it as a potential target for therapeutic blockade.

scholarly journals Antagonizing Deactivating Cytokines To Enhance Host Defense and Chemotherapy in Experimental Visceral Leishmaniasis

2005 ◽  
Vol 73 (7) ◽  
pp. 3903-3911 ◽  
Author(s):  
Henry W. Murray ◽  
Kathleen C. Flanders ◽  
Debra D. Donaldson ◽  
Joseph P. Sypek ◽  
Philip J. Gotwals ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Th1 Cell ◽  
Pentavalent Antimony ◽  
Ifn Γ ◽  
Liver Infection

ABSTRACT In experimental visceral leishmaniasis, inhibition of interleukin 10 (IL-10) signaling enhances Th1-cell-associated responses, promoting gamma interferon (IFN-γ) secretion, granuloma assembly, macrophage activation with substantial liver parasite killing, and synergy with pentavalent antimony (Sb) chemotherapy. To determine if inhibiting other suppressive cytokines has similar therapeutic potential, Leishmania donovani-infected BALB/c mice were injected with anti-IL-4 monoclonal antibody or receptor fusion antagonists of IL-13 or transforming growth factor β (TGF-β). Targeting IL-13 or TGF-β enabled inhibition of L. donovani replication but little parasite killing; anti-IL-4 had no effect. None of the three antagonists promoted IFN-γ production, granuloma maturation, or Sb efficacy. Excess IL-13 and TGF-β exacerbated liver infection; however, effects were transient. Among IL-10, IL-4, IL-13, and TGF-β, cytokines capable of disabling Th1-cell mechanisms (including those which support chemotherapy), IL-10 appears to be the appropriate target for therapeutic inhibition in visceral L. donovani infection.

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