Experimental Cutaneous Leishmaniasis: Mouse Models for Resolution of Inflammation Versus Chronicity of Disease

Bogdan, Christian; Debus, Andrea; Sebald, Heidi; Rai, Baplu; Schäfer, Johanna; Obermeyer, Stephanie; Schleicher, Ulrike

doi:10.1007/978-1-4939-9210-2_18

Cited by 6 publications

(9 citation statements)

References 94 publications

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“…For infection, stationary-phase L. major promastigotes (strain MHOM/IL/81/FEBNI) were used. Origin and culturing of the parasites were described elsewhere [ 6 , 58 ]. Mice were either infected intradermally (i.d.)…”

Section: Methodsmentioning

confidence: 99%

“…The course of infection is determined by the parasite species and by the innate and adaptive immune response of the infected host organisms [ 3 , 4 , 5 ]. Over the past decades, experiments with the C57BL/6 mouse strain have yielded valuable insights into the key cellular, soluble and enzymatic factors that are critical for the control of Leishmania (L.) major , a parasite species that elicits cutaneous leishmaniasis [ 6 ]. The resolution of disease depends on dendritic cells [ 7 , 8 ] and type 1 T helper cells (Th1) [ 3 , 5 ], which release interferon (IFN)-γ and tumor necrosis factor (TNF) and thereby cause classical macrophage activation characterized by the expression of inducible or type 2 nitric oxide (NO) synthase (iNOS, NOS2) [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Unlike C57BL/6 mice, BALB/c mice develop non-healing and progressive cutaneous as well as visceral disease following L. major infection. Consequently, BALB/c mice have served as a model to define immunological processes that promote disease [ 3 , 6 ]. An essential parameter that is causatively linked to non-healing L. major infections is the production of interleukin (IL)-4.…”

Section: Introductionmentioning

confidence: 99%

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Eosinophils, but Not Type 2 Innate Lymphoid Cells, Are the Predominant Source of Interleukin 4 during the Innate Phase of Leishmania major Infection

et al. 2022

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Interleukin (IL)-4 plays a central role in the initiation of a type 2 T helper cell (Th2) response, which leads to non-healing and progressive infections with the protozoan parasite Leishmania (L.) major. Here, we tested the hypothesis that type 2 innate lymphoid cells (ILC2), which promote the development of Th2 cells, form an important source of IL-4 early after intradermal or subcutaneous L. major infection. Lineage-marker negative CD90.2+CD127+PD1− ILC2 were readily detectable in the ear or foot skin, but hardly in the draining lymph nodes of both naïve and L. major-infected self-healing C57BL/6 and non-healing BALB/c mice and made up approximately 20% to 30% of all CD45+SiglecF− cells. Dermal ILC2 of C57BL/6 mice expressed the inducible T cell-costimulator (ICOS, CD278), whereas BALB/C ILC2 were positive for the stem cell antigen (Sca)-1. Within the first 5 days of infection, the absolute numbers of ILC2 did not significantly change in the dermis, which is in line with the unaltered expression of cytokines activating (IL-18, IL-25, IL-33, TSLP) or inhibiting ILC2 (IL-27, IFN-γ). At day 5 to 6 post infection, we observed an upregulation of IL-4, but not of IL-5, IL-10 or IL-13 mRNA. Using IL-4-reporter (4get) mice, we found that the production of IL-4 by C57BL/6 or BALB/c mice was largely restricted to CD45+SiglecF+ cells of high granularity, i.e., eosinophils. From these data, we conclude that eosinophils, but not ILC2, are a major innate source of IL-4 at the skin site of L. major infection.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Eosinophils, but Not Type 2 Innate Lymphoid Cells, Are the Predominant Source of Interleukin 4 during the Innate Phase of Leishmania major Infection

et al. 2022

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“…L. major promastigote strain MHOM/IL/81/FEBNI was propagated in RPMI 1640 (10% fetal calf serum) on Novy-MacNeal-Nicolle blood agar slants for a maximum of five passages and used as described earlier ( 31 , 32 ). L. major promastigotes were collected from blood agar slants.…”

Section: Methodsmentioning

confidence: 99%

Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity

et al. 2022

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Local tissue acidosis affects anti-tumor immunity. In contrast, data on tissue pH levels in infected tissues and their impact on antimicrobial activity is sparse. In this study, we assessed the pH levels in cutaneous Leishmania lesions. Leishmania major-infected skin tissue displayed pH levels of 6.7 indicating that lesional pH is acidic. Next, we tested the effect of low extracellular pH on the ability of macrophages to produce leishmanicidal NO and to fight the protozoan parasite Leishmania major. Extracellular acidification led to a marked decrease in both NO production and leishmanicidal activity of lipopolysaccharide (LPS) and interferon γ (IFN-γ)-coactivated macrophages. This was not directly caused by a disruption of NOS2 expression, a shortage of reducing equivalents (NAPDH) or substrate (L-arginine), but by a direct, pH-mediated inhibition of NOS2 enzyme activity. Normalization of intracellular pH significantly increased NO production and antiparasitic activity of macrophages even in an acidic microenvironment. Overall, these findings indicate that low local tissue pH can curtail NO production and leishmanicidal activity of macrophages.

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“…Obtained suspensions were incubated in 96-well plates, and a 10-fold dilution was performed. After 14 days of incubation, wells were observed under an inverted microscope and the number of parasites was determined by the highest dilution where viable parasites were observed ( 28 ).…”

Section: Methodsmentioning

confidence: 99%

Identification of Immunodominant Antigens From a First-Generation Vaccine Against Cutaneous Leishmaniasis

et al. 2022

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Leishmaniasis is a neglected tropical disease (NTD) caused by parasites belonging to the Leishmania genus for which there is no vaccine available for human use. Thus, the aims of this study are to evaluate the immunoprotective effect of a first-generation vaccine against L. amazonensis and to identify its immunodominant antigens. BALB/c mice were inoculated with phosphate buffer sodium (PBS), total L. amazonensis antigens (TLAs), or TLA with Poly (I:C) and Montanide ISA 763. The humoral and cellular immune response was evaluated before infection. IgG, IgG1, and IgG2a were measured on serum, and IFN-γ, IL-4, and IL-10 cytokines as well as cell proliferation were measured on a splenocyte culture from vaccinated mice. Immunized mice were challenged with 104 infective parasites of L. amazonensis on the footpad. After infection, the protection provided by the vaccine was analyzed by measuring lesion size, splenic index, and parasite load on the footpad and spleen. To identify immunodominant antigens, total proteins of L. amazonensis were separated on 2D electrophoresis gel and transferred to a membrane that was incubated with serum from immunoprotected mice. The antigens recognized by the serum were analyzed through a mass spectrometric assay (LC-MS/MS-IT-TOF) to identify their protein sequence, which was subjected to bioinformatic analysis. The first-generation vaccine induced higher levels of antibodies, cytokines, and cell proliferation than the controls after the second dose. Mice vaccinated with TLA + Poly (I:C) + Montanide ISA 763 showed less footpad swelling, a lower splenic index, and a lower parasite load than the control groups (PBS and TLA). Four immunodominant proteins were identified by mass spectrometry: cytosolic tryparedoxin peroxidase, an uncharacterized protein, a kinetoplast-associated protein-like protein, and a putative heat-shock protein DNAJ. The identified proteins showed high levels of conserved sequence among species belonging to the Leishmania genus and the Trypanosomatidae family. These proteins also proved to be phylogenetically divergent to human and canine proteins. TLA + Poly (I:C) + Montanide ISA 763 could be used as a first-generation vaccine against leishmaniasis. The four proteins identified from the whole-protein vaccine could be good antigen candidates to develop a new-generation vaccine against leishmaniasis.

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Experimental Cutaneous Leishmaniasis: Mouse Models for Resolution of Inflammation Versus Chronicity of Disease

Cited by 6 publications

References 94 publications

Eosinophils, but Not Type 2 Innate Lymphoid Cells, Are the Predominant Source of Interleukin 4 during the Innate Phase of Leishmania major Infection

Eosinophils, but Not Type 2 Innate Lymphoid Cells, Are the Predominant Source of Interleukin 4 during the Innate Phase of Leishmania major Infection

Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity

Identification of Immunodominant Antigens From a First-Generation Vaccine Against Cutaneous Leishmaniasis

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