Tissue Requirements for Establishing Long-Term CD4+ T Cell–Mediated Immunity following <i>Leishmania donovani</i> Infection

Bunn, Patrick T.; Stanley, Amanda C.; Rivera, Fabian de Labastida; Mulherin, Alexander; Sheel, Meru; Alexander, C.; Faleiro, Rebecca J.; Amante, Fiona H.; de, Marcela Montes; Best, Shannon E.; James, Kylie R.; Kaye, Paul M.; Haque, Ashraful; Engwerda, Christian

doi:10.4049/jimmunol.1300768

Cited by 23 publications

(33 citation statements)

References 54 publications

(52 reference statements)

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“…In visceral infection with L. donovani , CD8 + T cells have been shown to be both protective and dispensable (40, 42). We determined IFN-γ and Granzyme B (GzB) production by CD8 + T cells following challenge with L. infantum and, similar to observations in BALB/c mice (24), found a very low frequency of IFN-γ + cells regardless of the site of analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cutaneous Infection with Leishmania major Mediates Heterologous Protection against Visceral Infection with Leishmania infantum

Romano

Doria

Mendez

et al. 2015

The Journal of Immunology

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Visceral Leishmaniasis (VL) is a fatal disease of the internal organs caused by the eukaryotic parasite Leishmania. Control of VL would best be achieved through vaccination. However, this has proven to be difficult partly because the correlates of protective immunity are not fully understood. In contrast, protective immunity against non-fatal cutaneous Leishmaniasis (CL) is well defined and mediated by rapidly recruited, IFN-γ-producing, Ly6C+CD4+ T cells at the dermal challenge site. Protection against CL is best achieved by prior infection or live vaccination with Leishmania major, termed leishmanization. A long-standing question is whether prior CL or leishmanization can protect against VL. Employing an intra-dermal challenge model in mice, we report that cutaneous infection with Leishmania major provides heterologous protection against visceral infection with Leishmania infantum. Protection was associated with a robust CD4+ T cell response at the dermal challenge site and in the viscera. In-vivo labeling of circulating cells revealed that increased frequencies of IFN-γ+CD4+ T cells at sites of infection is due to recruitment or retention of cells in the tissue, rather than increased numbers of cells trapped in the vasculature. Shortly after challenge IFN-γ producing cells were highly enriched for Ly6C+T-bet+ cells in the viscera. Surprisingly, this heterologous immunity was superior to homologous immunity mediated by prior infection with Leishmania infantum. Our observations demonstrate a common mechanism of protection against different clinical forms of leishmaniasis. The efficacy of leishmanization against VL may warrant the introduction of the practice in VL endemic areas or during outbreaks of disease.

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Section: Resultsmentioning

confidence: 99%

Cutaneous Infection with Leishmania major Mediates Heterologous Protection against Visceral Infection with Leishmania infantum

Romano

Doria

Mendez

et al. 2015

The Journal of Immunology

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“…Mice were sacrificed by CO 2 asphyxiation, at times indicated through text, and bled via cardiac puncture. Spleens and perfused livers were removed at the times indicated, and parasite burdens were determined from Diff-Quick-stained impression smears (Lab Aids, Narrabeen, Australia) and expressed as Leishman-Donovan units (number of amastigotes/1000 host nuclei multiplied by the organ weight in grams) (33). Liver tissue also was preserved in Tissue-Tek O.C.T.…”

Section: Ethics Statementmentioning

confidence: 99%

“…Liver and spleen MNC were prepared as described previously (33). Fluorescently conjugated mAbs against CD4 (GK1.5), CD8 (53-6.7), CD3ε (17A2), CD49b (DX5), NK1.1 (PK136), TCRb (H57-597), TCRg/d (GL3), CD11b (M1/70), Ly6C (HK1.4), Ly6G (1A8), GR-1 (RB6-8C5), F4/80 (C1:A3-1), B220 (RA3-6B2), CD11c (N418), CCR6 (29-2L17), IL-17A (TC11-18H10.1), and IFN-g (XMG1.2) were purchased from BioLegend (San Diego, CA).…”

Section: Flow Cytometry and Absmentioning

confidence: 99%

IL-17A–Producing γδ T Cells Suppress Early Control of Parasite Growth by Monocytes in the Liver

Sheel

Beattie

Frame

et al. 2015

The Journal of Immunology

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Intracellular infections, such as those caused by the protozoan parasite Leishmania donovani, a causative agent of visceral leishmaniasis (VL), require a potent host proinflammatory response for control. IL-17 has emerged as an important proinflammatory cytokine required for limiting growth of both extracellular and intracellular pathogens. However, there are conflicting reports on the exact roles for IL-17 during parasitic infections and limited knowledge about cellular sources and the immune pathways it modulates. We examined the role of IL-17 in an experimental model of VL caused by infection of C57BL/6 mice with L. donovani and identified an early suppressive role for IL-17 in the liver that limited control of parasite growth. IL-17–producing γδ T cells recruited to the liver in the first week of infection were the critical source of IL-17 in this model, and CCR2+ inflammatory monocytes were an important target for the suppressive effects of IL-17. Improved parasite control was independent of NO generation, but associated with maintenance of superoxide dismutase mRNA expression in the absence of IL-17 in the liver. Thus, we have identified a novel inhibitory function for IL-17 in parasitic infection, and our results demonstrate important interactions among γδ T cells, monocytes, and infected macrophages in the liver that can determine the outcome of parasitic infection.

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“…c). CD4 + T cells are important for the establishment and maintenance of anti‐parasitic immunity in the liver as well as immune surveillance and suppression of parasite outgrowth in the spleen in the murine model of VL . B cells have been shown to promote parasite persistence and to be involved in dampening neutrophil‐mediated inflammatory responses in the C57BL/6 model .…”

Section: Resultsmentioning

confidence: 99%

In vivo characterization of two additional Leishmania donovani strains using the murine and hamster model

Kauffmann

Dumetz

Hendrickx

et al. 2016

Parasite Immunology

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Leishmania donovani is a protozoan parasite causing the neglected tropical disease visceral leishmaniasis. One difficulty to study the immunopathology upon L. donovani infection is the limited adaptability of the strains to experimental mammalian hosts. Our knowledge about L. donovani infections relies on a restricted number of East African strains (LV9, 1S). Isolated from patients in the 1960s, these strains were described extensively in mice and Syrian hamsters and have consequently become 'reference' laboratory strains. L. donovani strains from the Indian continent display distinct clinical features compared to East African strains. Some reports describing the in vivo immunopathology of strains from the Indian continent exist. This study comprises a comprehensive immunopathological characterization upon infection with two additional strains, the Ethiopian L. donovani L82 strain and the Nepalese L. donovani BPK282 strain in both Syrian hamsters and C57BL/6 mice. Parameters that include parasitaemia levels, weight loss, hepatosplenomegaly and alterations in cellular composition of the spleen and liver, showed that the L82 strain generated an overall more virulent infection compared to the BPK282 strain. Altogether, both L. donovani strains are suitable and interesting for subsequent in vivo investigation of visceral leishmaniasis in the Syrian hamster and the C57BL/6 mouse model.

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Tissue Requirements for Establishing Long-Term CD4+ T Cell–Mediated Immunity following Leishmania donovani Infection

Cited by 23 publications

References 54 publications

Cutaneous Infection with Leishmania major Mediates Heterologous Protection against Visceral Infection with Leishmania infantum

Cutaneous Infection with Leishmania major Mediates Heterologous Protection against Visceral Infection with Leishmania infantum

IL-17A–Producing γδ T Cells Suppress Early Control of Parasite Growth by Monocytes in the Liver

In vivo characterization of two additional Leishmania donovani strains using the murine and hamster model

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