The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist

Kima, Peter E.

doi:10.1016/j.ijpara.2007.04.007

Cited by 139 publications

(108 citation statements)

References 91 publications

(91 reference statements)

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“…It is well established that internalization of amastigotes via phospatidylserine receptors on macrophages induces secretion of IL-10 and TGF-b, which in turn blocks induction of iNOS, resulting in decreased production of NO (5). Studies in the classical hamster model of VL also showed decreased expression of iNOS mRNA, accounting for defective parasite elimination, thereby enhancing disease progression (47).…”

Section: Parasitized Macrophages Had Decreased Levels Of No That Was mentioning

confidence: 99%

Monitoring of intracellular nitric oxide in leishmaniasis: Its applicability in patients with visceral leishmaniasis

et al. 2010

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Nitric oxide (NO) has been demonstrated to be a principal effector molecule responsible for mediating intracellular killing of Leishmania parasites, the causative organism of leishmaniasis. As measurement of intracellular NO remains a challenge to biologists, we have developed a flow cytometric approach to perform real time biological detection of NO within Leishmania parasites and parasitized macrophages using a membrane permeable derivative of diaminofluorescein [4,5-diaminofluorescein diacetate (DAF-2DA)]. Initially, assay optimization was performed in Leishmania donovani promastigotes, assay specificity being confirmed using both a NO donor [S-nitroso-N-acetyl-penicillamine (SNAP)] and a NO scavenger [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, C-PTIO]. Using 40 lM DAF-2DA, basal levels of intracellular NO were measured which varied in different Leishmania species; addition of conventional anti-leishmanial drugs, antimony and miltefosine translated into a dramatic increase in DAF-2T fluorescence. Furthermore, the assay also measured levels of NO in macrophages, but needed a 20 fold lower concentration of DAF-2DA, being 2 lM. Following parasitization, levels of NO decreased which was normalized following treatment with anti-leishmanial drugs. Similarly monocytes of patients with visceral leishmaniasis at disease presentation showed decreased levels of NO which too reverted on completion of treatment. Taken together, this study opens new perspectives of research regarding monocyte function and provides a real time approach for monitoring the effect of anti-leishmanial compounds. ' International Society for Advancement of Cytometry Key termsanti-leishmanial; DAF-2DA; flow cytometry; leishmaniasis; nitric oxide LEISHMANIA are intracellular protozoan parasites that infect host mononuclear phagocytes, the resultant complex of diseases being leishmaniasis affecting 12 million people world wide in 88 countries (1). This disease is characterized by development of dermal lesions that may be cutaneous leishmaniasis (CL), diffuse cutaneous leishmaniasis (DCL), or mucocutaneous leishmaniasis (MCL) as also there can be systemic involvement as in the case of visceral leishmaniasis (VL), which is potentially fatal if left untreated (2).This obligate intracellular parasite resides and multiplies within macrophages, and therefore it should be able to evade the cytotoxic mechanisms innately operative within the macrophages for its survival (3). One of the predominant cytotoxic mechanisms includes production of reactive nitrogen intermediates, which the Leishmania parasite effectively decreases to ensure its survival (4,5).

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Section: Parasitized Macrophages Had Decreased Levels Of No That Was mentioning

confidence: 99%

Monitoring of intracellular nitric oxide in leishmaniasis: Its applicability in patients with visceral leishmaniasis

et al. 2010

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“…In fact an important mechanism through which TGF-b suppresses effector T cells is the promotion of regulatory T cells (Tregs) maintenance and differentiation [3,4]. TGF-b was shown to be involved in the expansion of both native and induced Foxp3 þ Tregs in malaria [5e7], toxoplasmosis [8], and leishmaniasis [9]. Both TCR-dependent and independent mechanisms have been demonstrated to account for Treg expansion during parasitic infections [10,11].…”

Section: Introductionmentioning

confidence: 99%

Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes

Clemente

Severini

Castronovo

et al. 2014

Microbes and Infection

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Interference with transforming growth factor-b-mediated pathways helps several parasites to survive for long periods in immunocompetent hosts. Macrophages and dendritic cells infected by Toxoplasma, Leishmania and Plasmodium spp. produce large amounts of transforming growth factor-b and induce the differentiation of antigen-specific T-regulatory cells. Mechanisms not mediated by antigen-presentation could also account for the expansion of T-regulatory cells in parasitic diseases and they also might be mediated through transforming growth factor-breceptor activated pathways. We explored the properties of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites, Trichinella spiralis muscle larvae to expand the pool of T-regulatory cells in a population of polyclonally activated T cells in the absence of accessory cells, and compared their effects to those induced by Plasmodium falciparum extracts. Similarly to P. falciparum, L. infantum extracts activate the latent soluble form of transforming growth factor-b and that bound to the membrane of activated T lymphocytes. The interaction of the active cytokine with transforming growth factor-b receptor induces Foxp3 expression by activated lymphocytes, favoring their conversion through the T-regulatory phenotype. Both Toxoplasma gondii and L. infantum extracts are able to induce transforming growth factor-b production by activated T cells in the absence of accessory cells.

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“…Extensive studies have been conducted to examine how Leishmania promastigotes (the insect stage of the parasite) and amastigotes (the intracellular form) infect target cells and suppress the intracellular signaling events in macrophages [reviewed by (Kima, 2007) and ]. However, limited information is available regarding the molecular details as to how DCs respond to the intracellular amastigotes.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Luo

Soong

2008

Molecular Immunology

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We have previously reported a link between a deficient Th1 response to Leishmania amazonensis (La) parasites and profound impairments in the cytokine/chemokine network at early stages of the infection. To define the molecular basis of these deficiencies, we focused on early and intracellular events in La-infected dendritic cells (DCs) in this study. Compared with La promastigote-infected counterparts, amastigote-infected DCs were less mature and less potent as antigen-presenting cells (APC) as evidenced by the lower expression of CD40 and CD83, suppressed cytokine expression (IL-12p40 and IL-10), reduced effectiveness for priming CD4 + T cells from naïve or infected mice. Infection with La promastigotes, but not amastigotes, triggered transient expression of IL-12p40 by DC. Both forms of parasites markedly suppressed IL-12p40, IL-12p70, and IL-6 production and increased IL-10 production when DCs were treated with LPS, IFN-γ/LPS or IFN-α/LPS as positive stimuli. Of note, pre-infection of DCs with live amastigotes resulted in multiple alterations in innate signaling pathways, including degradation of STAT2, decreased phosphorylation of STAT1, 2, 3 and ERK1/2, and markedly reduced expression of interferon regulatory factor-1 (IRF-1) and IRF-8, some of which were partially reversed by pretreatment of parasites with proteasome or protease inhibitors. The impaired IL-12 production in infected DCs was not attributed to increased IL-10 production. Together, our data suggest that La parasites, especially in their intracellular forms, have evolved unique strategies to actively downregulate early innate signaling events, resulting in impaired DC function and Th1 activation.

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The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist

Cited by 139 publications

References 91 publications

Monitoring of intracellular nitric oxide in leishmaniasis: Its applicability in patients with visceral leishmaniasis

Monitoring of intracellular nitric oxide in leishmaniasis: Its applicability in patients with visceral leishmaniasis

Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

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