scholarly journals Murine Susceptibility to Leishmania amazonensis Infection Is Influenced by Arginase-1 and Macrophages at the Lesion Site

2021 ◽  
Vol 11 ◽  
Author(s):  
Fernanda Tomiotto-Pellissier ◽  
Milena Menegazzo Miranda-Sapla ◽  
Taylon Felipe Silva ◽  
Bruna Taciane da Silva Bortoleti ◽  
Manoela Daiele Gonçalves ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Adoptive Transfer ◽  
Leishmania Amazonensis ◽  
Type Iii Collagen ◽  
M2 Macrophage ◽  
Self Healing ◽  
Lesion Site ◽  
Effective Response ◽  
Pronounced Increase ◽  
Arginase 1

Cutaneous leishmaniasis is a zoonotic infectious disease broadly distributed worldwide, causing a range of diseases with clinical outcomes ranging from self-healing infections to chronic disfiguring disease. The effective immune response to this infection is yet to be more comprehensively understood and is fundamental for developing drugs and vaccines. Thus, we used experimental models of susceptibility (BALB/c) and partial resistance (C57BL/6) to Leishmania amazonensis infection to investigate the local profile of mediators involved in the development of cutaneous leishmaniasis. We found worse disease outcome in BALB/c mice than in C57BL/6 mice, with almost 15 times higher parasitic load, ulcerated lesion formation, and higher levels of IL-6 in infected paws. In contrast, C57BL/6 presented higher levels of IFN-γ and superoxide anion (•O2−) after 11 weeks of infection and no lesion ulcerations. A peak of local macrophages appeared after 24 h of infection in both of the studied mice strains, followed by another increase after 240 h, detected only in C57BL/6 mice. Regarding M1 and M2 macrophage phenotype markers [iNOS, MHC-II, CD206, and arginase-1 (Arg-1)], we found a pronounced increase in Arg-1 levels in BALB/c after 11 weeks of infection, whereas C57BL/6 showed an initial predomination of markers from both profiles, followed by an M2 predominance, coinciding with the second peak of macrophage infiltration, 240 h after the infection. Greater deposition of type III collagen and lesion resolution was also observed in C57BL/6 mice. The adoptive transfer of macrophages from C57BL/6 to infected BALB/c at the 11th week showed a reduction in both edema and the number of parasites at the lesion site, in addition to lower levels of Arg-1. Thus, C57BL/6 mice have a more effective response against L. amazonensis, based on a balance between inflammation and tissue repair, while BALB/c mice have an excessive Arg-1 production at late infection. The worst evolution seems to be influenced by recruitment of Arg-1 related macrophages, since the adoptive transfer of macrophages from C57BL/6 mice to BALB/c resulted in better outcomes, with lower levels of Arg-1.

scholarly journals DNA Immunization with the Gene Encoding P4 Nuclease of Leishmania amazonensis Protects Mice against Cutaneous Leishmaniasis

2003 ◽  
Vol 71 (11) ◽  
pp. 6270-6278 ◽  
Author(s):  
Kimberly Campbell ◽  
Hong Diao ◽  
Jiaxiang Ji ◽  
Lynn Soong
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Protozoan Parasite ◽  
Leishmania Amazonensis ◽  
Interleukin 12 ◽  
Self Healing ◽  
Dna Encoding ◽  
Gene Encoding ◽  
Necrosis Factor Alpha ◽  
Log Reduction ◽  
Factor Alpha

ABSTRACT Infection with the protozoan parasite Leishmania amazonensis can cause diverse clinical forms of leishmaniasis. Immunization with purified P4 nuclease protein has been shown to elicit a protective response in mice challenged with L. amazonensis and L. pifanoi. To explore the potential of a DNA-based vaccine, we tested the L. amazonensis gene encoding P4 nuclease as well as adjuvant constructs encoding murine interleukin-12 (IL-12) and L. amazonensis HSP70. Susceptible BALB/c mice were immunized with the DNA encoding P4 alone, P4/IL-12, or P4/HSP70 prior to challenge with L. amazonensis promastigotes. Mice given P4/IL-12 exhibited no lesion development and had a 3- to 4-log reduction in tissue parasite burdens compared to controls. This protection corresponded to significant increases in gamma interferon and tumor necrosis factor alpha production and a reduction in parasite-specific immunoglobulin G1, suggesting an enhancement in Th1 responses. Moreover, we immunized mice with the L. amazonensis vaccines to determine if this vaccine regimen could provide cross-protection against a genetically diverse species, L. major. While the P4/HSP70 vaccine led to self-healing lesions, the P4/IL-12 vaccine provided negligible protection against L. major infection. This is the first report of successful use of a DNA vaccine to induce protection against L. amazonensis infection. Additionally, our results indicate that different vaccine combinations, including DNA encoding P4, HSP70, or IL-12, can provide significant protection against both Old World and New World cutaneous leishmaniasis.

scholarly journals Efficacy of topical risedronate and risedronate - Eudragit E complex in a model of cutaneous leishmaniasis induced by Leishmania (Leishmania) amazonensis

Heliyon ◽  
2021 ◽  
Vol 7 (5) ◽  
pp. e07136
Author(s):  
Ma. Florencia Peralta ◽  
Ma. Laura Guzman ◽  
Ma. Estefanía Bracamonte ◽  
J. Diego Marco ◽  
Ma. Eugenia Olivera ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Amazonensis ◽  
Eudragit E

A new focus of cutaneous leishmaniasis due to Leishmania amazonensis in a Sub Andean region of Bolivia

Acta Tropica ◽  
1998 ◽  
Vol 71 (2) ◽  
pp. 97-106 ◽  
Author(s):  
E Martı́nez ◽  
F Le Pont ◽  
M Torrez ◽  
J Tellerı́a ◽  
F Vargas ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Amazonensis ◽  
Andean Region

scholarly journals Protection of C57BL/10 mice by vaccination with association of purified proteins from Leishmania (Leishmania) amazonensis

1999 ◽  
Vol 41 (4) ◽  
pp. 243-248 ◽  
Author(s):  
Ana Mariela MORA ◽  
Wilson MAYRINK ◽  
Roberto Teodoro da COSTA ◽  
Carlos Alberto da COSTA ◽  
Odair GENARO ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Crude Extract ◽  
Gel Electrophoresis ◽  
Protective Immunity ◽  
Polyacrylamide Gel Electrophoresis ◽  
Challenge Infection ◽  
Leishmania Amazonensis ◽  
The Past ◽  
Specific Stimulation ◽  
Stimulation Of

In the past few years, induction of protective immunity to cutaneous leishmaniasis has been attempted by many researchers using a variety of antigenic preparations, such as living promastigotes or promastigote extracts, partially purified, or defined proteins. In this study, eleven proteins from Leishmania (Leishmania) amazonensis (LLa) with estimated molecular mass ranging from 97 to 13.5kDa were isolated by polyacrylamide gel electrophoresis and electro-elution. The proteins were associated as vaccine in different preparations with gp63 and BCG (Bacilli Calmette-Guérin). The antigenicity of these vaccines was measured by their ability to induce the production of IFN-<FONT FACE="Symbol">g</font> by lymphocyte from subjects vaccinated with Leishvacin<FONT FACE="Symbol">â</font> . The immunogenicity was evaluated in vaccinated mice. C57BL/10 mice were vaccinated with three doses of each vaccine consisting of 30 <FONT FACE="Symbol">m</font>g of each protein at 15 days interval. One hundred <FONT FACE="Symbol">m</font>g of live BCG was only used in the first dose. Seven days after the last dose, they received a first challenge infection with 105 infective promastigotes and four months later, a second challenge was done. Two months after the second challenge, 42.86% of protection was obtained in the group of mice vaccinated with association of proteins of gp63+46+22kDa, gp63+13.5+25+42kDa, gp63+46+42kDa, gp63+66kDa, and gp63+97kDa; 57.14% of protection was demonstrated with gp63+46+97+13.5kDa, gp63+46+97kDa, gp63+46+33kDa, and 71.43% protection for gp63 plus all proteins. The vaccine of gp63+46+40kDa that did not protect the mice, despite the good specific stimulation of lymphocytes (LSI = 7.60) and 10.77UI/ml of IFN-<FONT FACE="Symbol">g</font> production. When crude extract of L. (L.) amazonensis was used with BCG a 57.14% of protection was found after the first challenge and 28.57% after the second, the same result was observed for gp63. The data obtained with the vaccines can suggest that the future vaccine probably have to contain, except the 40kDa, a cocktail of proteins that would protect mice against cutaneous leishmaniasis.

scholarly journals Evaluation of different total Leishmania amazonensis antigens for the development of a first-generation vaccine formulated with a Toll-like receptor-3 agonist to prevent cutaneous leishmaniasis

2020 ◽  
Vol 115 ◽  
Author(s):  
María José Germanó ◽  
Esteban Sebastián Lozano ◽  
María Victoria Sanchez ◽  
Flavia Alejandra Bruna ◽  
María Fernanda García-Bustos ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
First Generation ◽  
Leishmania Amazonensis ◽  
Toll Like Receptor ◽  
Generation Vaccine

scholarly journals Macrophage Polarization in the Skin Lesion Caused by Neotropical Species of Leishmania sp

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Carmen M. Sandoval Pacheco ◽  
Gabriela V. Araujo Flores ◽  
Kadir Gonzalez ◽  
Claudia M. de Castro Gomes ◽  
Luiz F. D. Passero ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Macrophage Polarization ◽  
Leishmania Species ◽  
Skin Lesions ◽  
Host Cells ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Intracellular Parasites ◽  
Skin Biopsies ◽  
Acquired Immune Responses

Macrophages play important roles in the innate and acquired immune responses against Leishmania parasites. Depending on the subset and activation status, macrophages may eliminate intracellular parasites; however, these host cells also can offer a safe environment for Leishmania replication. In this sense, the fate of the parasite may be influenced by the phenotype of the infected macrophage, linked to the subtype of classically activated (M1) or alternatively activated (M2) macrophages. In the present study, M1 and M2 macrophage subsets were analyzed by double-staining immunohistochemistry in skin biopsies from patients with American cutaneous leishmaniasis (ACL) caused by L. (L.) amazonensis, L. (V.) braziliensis, L. (V.) panamensis ,and L. (L.) infantum chagasi. High number of M1 macrophages was detected in nonulcerated cutaneous leishmaniasis (NUCL) caused by L. (L.) infantum chagasi ( M 1 = 112 ± 12 , M 2 = 43 ± 12 cells/mm2). On the other side, high density of M2 macrophages was observed in the skin lesions of patients with anergic diffuse cutaneous leishmaniasis (ADCL) ( M 1 = 195 ± 25 , M 2 = 616 ± 114 ), followed by cases of localized cutaneous leishmaniasis (LCL) caused by L. (L.) amazonensis ( M 1 = 97 ± 24 , M 2 = 219 ± 29 ), L. (V.) panamensis ( M 1 = 71 ± 14 , M 2 = 164 ± 14 ), and L. (V.) braziliensis ( M 1 = 50 ± 13 , M 2 = 53 ± 10 ); however, low density of M2 macrophages was observed in NUCL. The data presented herein show the polarization of macrophages in skin lesions caused by different Leishmania species that may be related with the outcome of the disease.

scholarly journals Endlicheria bracteolata (Meisn.) Essential Oil as a Weapon Against Leishmania amazonensis: In Vitro Assay

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2525 ◽  
Author(s):  
Mariana Margatto Rottini ◽  
Ana Claudia Fernandes Amaral ◽  
José Luiz Pinto Ferreira ◽  
Edinilze Souza Coelho Oliveira ◽  
Jefferson Rocha de Andrade Silva ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Flow Cytometry ◽  
Essential Oil ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Amazonensis ◽  
Vitro Assay ◽  
Transmission Electron ◽  
Biological Potential ◽  
Intracellular Amastigote

The difficulties encountered and the numerous side effects present in the treatment of cutaneous leishmaniasis have encouraged the research for new compounds that can complement or replace existing treatment. The growing scientific interest in the study of plants, which are already used in folk remedies, has led our group to test Endlicheria bracteolata essential oil against Leishmania amazonensis. Several species of the Lauraceae family, or their compounds, have relevant antiprotozoal activities Therefore, the biological potential on L. amazonensis forms from the essential oil of Endlicheria bracteolata leaves was verified for the first time in that work. The antileishmanial activity was evaluated against promastigotes and intracellular amastigotes, and cytotoxicity were performed with J774.G8, which were incubated with different concentrations of E. bracteolata essential oil. Transmission electron microscopy and flow cytometry were performed with E. bracteolata essential oil IC50. Promastigote forms showed E. bracteolata essential oil IC50 of 7.945 ± 1.285 µg/mL (24 h) and 6.186 ± 1.226 µg/mL (48 h), while for intracellular amastigote forms it was 3.546 ± 1.184 µg/mL (24 h). The CC50 was 15.14 ± 0.090 µg/mL showing that E. bracteolata essential oil is less toxic to macrophages than to parasites. Transmission electron microscopy showed that E. bracteolata essential oil treatment is capable of inducing mitochondrial damage to promastigote and intracellular amastigote forms, while flow cytometry showed ΔѰm disruption in treated parasites. These results could bring about new possibilities to develop products based on E. bracteolata essential oil to treat cutaneous leishmaniasis, especially for people who cannot receive the conventional therapy.

scholarly journals Differential Regulation of L-Arginine Metabolism through Arginase 1 during Infection with Leishmania mexicana Isolates Obtained from Patients with Localized and Diffuse Cutaneous Leishmaniasis

2020 ◽  
Vol 88 (7) ◽  
Author(s):  
Arturo A. Wilkins-Rodríguez ◽  
Armando Pérez-Torres ◽  
Alma R. Escalona-Montaño ◽  
Laila Gutiérrez-Kobeh
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Clinical Manifestations ◽  
Differential Regulation ◽  
Leishmania Mexicana ◽  
Arginine Metabolism ◽  
Content Type ◽  
Arginase 1 ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACT l-Arginine metabolism through arginase 1 (Arg-1) and inducible nitric oxide synthase (NOS2) constitutes a fundamental axis for the resolution or progression of leishmaniasis. Infection with Leishmania mexicana can cause two distinct clinical manifestations: localized cutaneous leishmaniasis (LCL) and diffuse cutaneous leishmaniasis (DCL). In this work, we analyzed in an in vivo model the capacity of two L. mexicana isolates, one obtained from a patient with LCL and the other from a patient with DCL, to regulate the metabolism of l-arginine through Arg-1 and NOS2. Susceptible BALB/c mice were infected with L. mexicana isolates from both clinical manifestations, and the evolution of the infection as well as protein presence and activity of Arg-1 and NOS2 were evaluated. The lesions of mice infected with the DCL isolate were bigger, had higher parasite loads, and showed greater protein presence and enzymatic activity of Arg-1 than the lesions of mice infected with the LCL isolate. In contrast, NOS2 protein synthesis was poorly or not induced in the lesions of mice infected with the LCL or DCL isolate. The immunochemistry analysis of the lesions allowed the identification of highly parasitized macrophages positive for Arg-1, while no staining for NOS2 was found. In addition, we observed in lesions of patients with DCL macrophages with higher parasite loads and stronger Arg-1 staining than those in lesions of patients with LCL. Our results suggest that L. mexicana isolates obtained from patients with LCL or DCL exhibit different virulence or pathogenicity degrees and differentially regulate l-arginine metabolism through Arg-1.

scholarly journals TissueGene-C promotes an anti-inflammatory micro-environment in a rat monoiodoacetate model of osteoarthritis via polarization of M2 macrophages leading to pain relief and structural improvement

2020 ◽  
Vol 28 (5) ◽  
pp. 1237-1252
Author(s):  
Hyeonyoul Lee ◽  
Heungdeok Kim ◽  
Jinwon Seo ◽  
Kyoungbaek Choi ◽  
Yunsin Lee ◽  
...  
Keyword(s):  
Pain Relief ◽  
Transforming Growth Factor ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Long Term Effects ◽  
Structural Improvement ◽  
Arginase 1 ◽  
Anti Inflammatory ◽  
Tgf Β1 ◽  
And Cartilage

Abstract Osteoarthritis (OA) is the most common form of arthritis, characterized by cartilage destruction, pain and inflammation in the joints. Existing medications can provide relief from the symptoms, but their effects on the progression of the disease are limited. TissueGene-C (TG-C) is a novel cell and gene therapy for the treatment of OA, comprising a mixture of human allogeneic chondrocytes and irradiated cells engineered to overexpress transforming growth factor-β1 (TGF-β1). This study aims to investigate the efficacy and mechanism of action of TG-C in a rat model of OA. Using the monosodium-iodoacetate (MIA) model of OA, we examined whether TG-C could improve OA symptoms and cartilage structure in rats. Our results showed that TG-C provided pain relief and cartilage structural improvement in the MIA OA model over 56 days. In parallel with these long-term effects, cytokine profiles obtained on day 4 revealed increased expression of interleukin-10 (IL-10), an anti-inflammatory cytokine, in the synovial lavage fluid. Moreover, the increased levels of TGF-β1 and IL-10 caused by TG-C induced the expression of arginase 1, a marker of M2 macrophages, and decreased the expression of CD86, a marker of M1 macrophages. These results suggest that TG-C exerts a beneficial effect on OA by inducing a M2 macrophage-dominant micro-environment. Cell therapy using TG-C may be a promising strategy for targeting the underlying pathogenic mechanisms of OA, reducing pain, improving function, and creating a pro-anabolic micro-environment. This environment supports cartilage structure regeneration and is worthy of further evaluation in future clinical trials.

scholarly journals Loss of ubiquitin-conjugating enzyme E2 (Ubc9) in macrophages exacerbates multiple low-dose streptozotocin-induced diabetes by attenuating M2 macrophage polarization

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Faxi Wang ◽  
Fei Sun ◽  
Jiahui Luo ◽  
Tiantian Yue ◽  
Longmin Chen ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Low Dose ◽  
Macrophage Polarization ◽  
Diabetes Incidence ◽  
M2 Macrophage ◽  
Macrophage Function ◽  
Arginase 1 ◽  
Ubiquitin Conjugating Enzyme ◽  
The Impact ◽  
Conjugating Enzyme

AbstractType 1 diabetes (T1D) is characterized by the selective autoimmune destruction of the islet β cells, and macrophages play a significant role in this process. Small ubiquitin-like modification (SUMOylation) is an important posttranslational modification involved in T1D pathogenesis, but its function in macrophages remains unexplored. We presently developed and used macrophage-specific ubiquitin-conjugating enzyme E2 (Ubc9) knockout (LyzM-Cre-Ubc9fl/fl, KO) mice to address the impact of SUMOylation on macrophage function in a T1D model. We observed that blocking Ubc9 in macrophages exacerbated multiple-low dose streptozotocin (MLD-STZ)-induced diabetes. Specifically, after STZ treatment, blood glucose levels were consistently elevated in the KO mice. The KO mice exhibited a higher diabetes incidence than WT controls (85% vs. 55%, P < 0.01) along with a higher insulitis severity. The loss of Ubc9 impaired macrophage energy metabolism and attenuated macrophage M2 program, thereby enhancing T cell activation. Pancreas-resident macrophages, rather than migrant macrophages, played a predominant role in MLD-STZ-induced diabetes. Mechanistically, Ubc9-mediated SUMOylation of interferon regulator factor 4 (IRF4) enhanced its nuclear localization and stability, thereby transcribing IL-4 and arginase 1 (Arg1) to promote the macrophage M2 program. Ubc9-mediated SUMOylation modulates T1D risk at least in part by regulating macrophage function. Modulation of disturbed SUMOylation process in macrophages, either through cell adoptive transfer or targeted drug-delivery, could help to establish a tolerant pancreatic microenvironment and promote inflammation resolution in early insulitis stage, thus hindering T1D progression.

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