Kupffer cells heterogeneity and replacement by monocyte-derived KCs contributes to visceral leishmaniasis resistance
Gabriela PessendaAndrea PaunTiago Rodrigues FerreiraEduardo P. AmaralJuraj KabátOlena KamenyevaSundar GanesanSang Hun LeeDavid L. Sacks
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Abstract Visceral leishmaniasis (VL) is a potentially fatal disease transmitted by sand fly bites and caused by Leishmania (L. donovani/L. infantum) protozoa. Kupffer cells (KCs) are the liver embryonic resident macrophages (emKCs), characterized by Clec4f and Tim4 expression and their sessile behavior within the liver sinusoids. KCs maintain their numbers via self-proliferation during homeostasis but can be replaced by monocyte-derived cells (moKCs) during inflammation. In the murine VL model, KCs are important for both initial parasite growth and granuloma formation, the latter being associated with the eventual protective response. The objective of our study is to investigate KC proliferation, migration, death, and their replacement by moKCs in VL. We found that KC proliferation was enhanced at 19 d.p.i., while at 42 d.p.i. the granulomas cores contained mixed KC clonal lineages and were located outside the liver sinusoids. At the same time point, Clec4f and Tim4 expression was reduced, and we found evidence of KC apoptosis and ferroptosis. Parabiotic mice demonstrated KC populations that bore either congenic marker, and CCR2 −/−infected mice showed enhanced frequencies of emKCs, reduced frequencies of moKCs, and higher parasite loads compared to WT mice. Reduction of ferroptosis in BACH1 −/−mice resulted in lower frequencies of moKCs. Collectively, our data indicates that KCs migrate to the liver parenchyma to form granulomas, facilitating their activation by other immune cells, and that KC death results in their partial replacement by moKCs, contributing to increased parasite killing. Thus, KC heterogeneity is an important hallmark of hepatic resistance in VL. Funded by the Division of Intramural Research, NIAID.Keywords:
Kupffer cell
Parenchyma
Monocyte
CD11c
The persistence of anti-Leishmania donovani antibodies in past visceral leishmaniasis (VL) cases was retrospectively assessed by means of the direct agglutination test (DAT) and the rK39 enzyme-linked immunosorbent assay (ELISA). Antibody titers remained high for an extended period of time in past cases of VL. These results highlight the need to carefully elicit the history of patients with VL symptoms.
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Twenty Kenyan patients with visceral leishmaniasis were evaluated for the presence of Leishmania donovani in their peripheral blood. Smears, cultures and hamster inoculations detected parasitaemia in 11, 10 and six patients, respectively, and at least one method detected parasitaemia in 15 patients (75%). The likelihood of detecting parasitaemia correlated with the density of parasites in splenic aspirate smears. It is apparent that parasitaemia with L. donovani occurs frequently in Kenyan patients with visceral leishmaniasis.
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ABSTRACT Leishmania donovani in India causes visceral infection (kala-azar) and dermal infection (post-kala-azar dermal leishmaniasis). We report here the identification of polymorphism in a well-defined genetic locus among the Leishmania parasites causing the visceral and dermal manifestations, in a comparison of 15 post-kala-azar dermal leishmaniasis and 12 kala-azar patient isolates.
Kinetoplastida
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(2008). Isolation and identification of Leishmania donovani from Phlebotomus orientalis, in an area of eastern Sudan with endemic visceral leishmaniasis. Annals of Tropical Medicine & Parasitology: Vol. 102, No. 6, pp. 553-555.
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In complement to a previous survey, the authors proceed to the analysis of strains isolated from visceral human and canine leishmaniasis. Finally, among eight human strains isolated and identified with an enzymatic method, seven belong to the Leishmania donovani complex and one to the L. infantum complex. The L. donovani complex is represented by the MON-31 and MON-83 zymodem. The first one is also present in Saudi Arabia and Ethiopia. The second one, corresponding to a small variant, pleads for an intrafocal polymorphism phenomenon which was until now unknown in the L. donovani complex. The L. infantum complex is observed: 1) in sympatria with L. donovani in mountainous areas; 2) alone in the Tihama coastal plain. As for human cutaneous leishmaniasis present in the same focuses it is caused by L. tropica MON-71 and not by the above mentioned complexes.
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Leishmania chagasi
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Abstract Visceral leishmaniasis is associated with hepato-splenomegaly and altered immune and haematological parameters in both pre-clinical animal models and humans. We studied mouse experimental visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani in BALB/c mice using dual RNA-seq to investigate the transcriptional response of host and parasite in liver and spleen. We identified only 4 species-specific parasite expressed genes (SSPEGs; log2FC >1, FDR <0.05) in the infected spleen, and none in the infected liver. For the host transcriptome, we found 789 differentially expressed genes (DEGs; log2FC >1, FDR <0.05) in the spleen that were common to both infections, with IFNγ signaling and complement and coagulation cascade pathways highly enriched, and an additional 286 and 186 DEGs that were selective to L. donovani and L. infantum infection respectively. Among those, there were network interactions between genes of amino acid metabolism and PPAR signaling in L. donovani infection and increased IL1β and positive regulation of fatty acid transport in L. infantum infection, although no pathway enrichment was observed. In the liver, there were 1939 DEGs in mice infected with either L. infantum or L. donovani in comparison to uninfected mice, and the most enriched pathways were IFNγ signaling, neutrophil mediated immunity, complement and coagulation, cytokine-chemokine responses and hemostasis. Additionally, 221 DEGs were selective in L. donovani and 429 DEGs in L. infantum infections. These data show that the host response for these two visceral leishmaniasis infection models is broadly similar, and ∼10% of host DEGs vary in infections with either parasite species. Importance Visceral leishmaniasis (VL) is caused by two species of Leishmania parasites, L. donovani in the Old World and L. infantum in the New World and countries bordering the Mediterranean. Although cardinal features such as hepato-splenomegaly and alterations in blood and immune function are evident, clinical presentation may vary by geography, with for example severe bleeding often associated with VL in Brazil. Although animal models of both L. donovani and L. infantum have been widely used to study disease pathogenesis, a direct side-by-side comparison of how these parasites species impact the infected host and/or how they might respond to the stresses of mammalian infection has not been previously reported. Identifying common and distinct pathways to pathogenesis will be important to ensure that new therapeutic or prophylactic approaches will be applicable across all forms of VL.
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