Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

Dalton, Jane E.; Maroof, Asher; Owens, Benjamin M. J.; Narang, Priyanka; Johnson, Katherine; Brown, Najmeeyah; Rosenquist, Lovisa; Beattie, Lynette; Coles, Mark; Kaye, Paul M.

doi:10.1172/jci41281

Cited by 46 publications

(58 citation statements)

References 79 publications

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“…Amongst common down-regulated DE genes, there was a significant enrichment in GO terms related to changes in morphology, pathways for anatomical structure morphogenesis (GO:0009653; FDR 3.22×10 -14 ) and vascular development (GO:0001944; 1.82×10 -11 ), the latter including negative regulators of angiogenesis such as Mmrn2 and promoters of angiogenesis such as Vegfa ( Figure 5D). These data are consistent with the notion that the well documented changes in vasculature associated with murine infection 9 also occur during hamster infection.…”

Section: Resultssupporting

confidence: 91%

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

Ashwin¹,

Seifert²,

Forrester³

et al. 2018

Wellcome Open Res

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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.

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Section: Resultssupporting

confidence: 91%

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

Ashwin¹,

Seifert²,

Forrester³

et al. 2018

Wellcome Open Res

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“…Meca-32 is a pan endothelial marker that recognizes red and white pulp vasculature and the endothelium of the marginal sinus in naïve mice 6 . As previously reported, 6 Meca-32 + vessels increased in abundance in the red pulp of mice infected with L. donovani (Figure 2A).…”

Section: Resultssupporting

confidence: 80%

Compartment-Specific Remodeling of Splenic Micro-Architecture during Experimental Visceral Leishmaniasis

Yurdakul

Dalton

Beattie

et al. 2011

The American Journal of Pathology

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Progressive splenomegaly is a hallmark of visceral leishmaniasis in humans, canids, and rodents. In experimental murine visceral leishmaniasis, splenomegaly is accompanied by pronounced changes in microarchitecture, including expansion of the red pulp vascular system, neovascularization of the white pulp, and remodeling of the stromal cell populations that define the B-cell and T-cell compartments. Here, we show that Ly6C/G+ (Gr-1+) cells, including neutrophils and inflammatory monocytes, accumulate in the splenic red pulp during infection. Cell depletion using monoclonal antibody against either Ly6C/G+ (Gr-1; RB6) or Ly6G+ (1A8) cells increased parasite burden. In contrast, depletion of Ly6C/G+ cells, but not Ly6G+ cells, halted the progressive remodeling of Meca-32+ and CD31+ red pulp vasculature. Strikingly, neither treatment affected white pulp neovascularization or the remodeling of the fibroblastic reticular cell and follicular dendritic cell networks. These findings demonstrate a previously unrecognized compartment-dependent selectivity to the process of splenic vascular remodeling during experimental murine visceral leishmaniasis, attributable to Ly6C+ inflammatory monocytes.

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“…As splenic infection progresses, the white pulp becomes shrunken and disorganized, and there is destruction of follicular DCs and loss of germinal centers. This destruction is associated with neovascularization and infiltration of the white pulp with heavily parasitized MΦs [132]. The neovascularization process was reversed to some degree by administration of the broadly acting receptor tyrosine kinase inhibitor, sunitinib, which also enhanced the generation of IFN-γ-producing Th1 cells [132].…”

Section: Mouse and Hamster Models Of Vlmentioning

confidence: 99%

“…This destruction is associated with neovascularization and infiltration of the white pulp with heavily parasitized MΦs [132]. The neovascularization process was reversed to some degree by administration of the broadly acting receptor tyrosine kinase inhibitor, sunitinib, which also enhanced the generation of IFN-γ-producing Th1 cells [132]. In parallel with the remodeling of the white pulp, there was also expansion of the red pulp vasculature, which was dependent on the influx of Ly6C + inflammatory monocytes [133].…”

Section: Mouse and Hamster Models Of Vlmentioning

confidence: 99%

Immunopathogenesis of non-healing American cutaneous leishmaniasis and progressive visceral leishmaniasis

2012

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The outcomes of Leishmania infection are determined by host immune and nutrition status, parasite species, and co-infection with other pathogens. While subclinical infection and self-healing cutaneous leishmaniasis (CL) are common, uncontrolled parasite replication can lead to non-healing local lesions or visceral leishmaniasis (VL). It is known that infection control requires Th1-differentiation cytokines (IL-12, IL-18, and IL-27) and Th1 cell and macrophage activation. However, there is no generalized consensus for the mechanisms of host susceptibility. The recent studies on regulatory T cells and IL-17-producing cells help explain the effector T cell responses that occur independently of the known Th1/Th2 cell signaling pathways. This review focuses on the immunopathogenesis of non-healing American CL and progressive VL. We summarize recent evidence from human and animal studies that reveals the mechanisms of dysregulated, hyper-responses to Leishmania braziliensis, as well as the presence of disease-promoting or the absence of protective responses to Leishmania amazonensis and Leishmania donovani. We highlight immune-mediated parasite growth and immunopathogenesis, with an emphasis on the putative roles of IL-17 and its related cytokines as well as arginase. A better understanding of the quality and regulation of innate immunity and T cell responses triggered by Leishmania will aid in the rational control of pathology and the infection.

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Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

Cited by 46 publications

References 79 publications

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

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

Compartment-Specific Remodeling of Splenic Micro-Architecture during Experimental Visceral Leishmaniasis

Immunopathogenesis of non-healing American cutaneous leishmaniasis and progressive visceral leishmaniasis

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