Abstract
Visceral leishmaniasis (VL), caused by infection with the intracellular protozoan Leishmania donovani, is a chronic progressive disease with a relentlessly increasing parasite burden in the spleen, liver and bone marrow. The disease is characterized by fever, splenomegaly, cachexia, and pancytopenia, and progresses to death if not treated. Control of Leishmania infection is mediated by Th1 (IFNγ-producing) CD4+ T cells, which activate macrophages to produce nitric oxide and kill intracellular parasites. However, despite expansion of CD4+ T cells and increased IFNγ expression in the spleen, humans with active VL do not control the infection. We used an experimental model of chronic progressive VL in hamsters, which mimics clinical and pathological features seen in humans, to better understand the mechanisms that lead to progressive disease. Transcriptional profiling of the spleen during chronic infection revealed expression of markers of both T cell activation and inhibition. CD4+ T cells isolated from the spleen during chronic progressive VL showed mixed expression of Th1 and Th2 cytokines and chemokines, and were marginally effective in controlling infection in an ex vivo T cell-macrophage co-culture system. Splenic CD4+ T cells and macrophages from hamsters with VL showed increased expression of inhibitory receptors and their ligands, respectively. Blockade of the inhibitory receptor PD-L2 led to a significant decrease in parasite burden, revealing a pathogenic role for the PD-1 pathway in chronic VL. PD-L2 blockade was associated with a dramatic reduction in expression of host arginase 1, but no change in IFNγ and inducible nitric oxide synthase. Thus, the expression of counter-regulatory molecules on splenic CD4+ T cells and macrophages promotes a more permissive macrophage phenotype and attenuates intracellular parasite control in chronic progressive VL. Host-directed adjunctive therapy targeting the PD-1 regulatory pathway may be efficacious for VL.
Highlights
Visceral leishmaniasis (VL) is a neglected tropical disease caused by the protozoan parasite Leishmania donovani or L. infantum (= L. chagasi)
To gain insight into the splenic gene expression involved in T cell function in progressive disease, we used unbiased transcriptional profiling (RNA sequencing) to identify pathways enriched in VL in 28 day infected hamsters
Using an experimental model that closely mimics active human disease, we found an increase in accumulation of CD4+ T cells with a mixed Th1/Th2 cytokine/chemokine profile in the spleen during chronic VL
Summary
Visceral leishmaniasis (VL) is a neglected tropical disease caused by the protozoan parasite Leishmania donovani or L. infantum (= L. chagasi). 90% of infected individuals experience asymptomatic infection without overt evidence of disease. The remainder of infected individuals develop a chronically progressive infection that principally involves the spleen, liver and bone marrow. Active VL is the most serious form of leishmaniasis, accounting for approximately 500,000 cases annually [3, 4]. It is usually fatal if not treated, and even with treatment, the mortality rate can be as high as 20% [3, 5]. Clinical symptoms include chronic fever, loss of appetite, cachexia, and enlarged liver and spleen. Patients with progressive VL have pancytopenia, and loss of antigen-induced lymphoproliferative and Th1 cytokine responses in peripheral blood mononuclear cell cultures [6, 7]
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