Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo

Kropf, Pascale; Fuentes, José; Fähnrich, Eva; Arpa, Luis; Herath, Shan; Weber, Verena; Soler, Germán; Celada, Antonio; Modolell, Manuel; Müller, Ingrid

doi:10.1096/fj.04-3416fje

Cited by 256 publications

(361 citation statements)

References 70 publications

(105 reference statements)

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“…In contrast to our observations using ⌬arg L. mexicana, pharmacological inhibition of arginase did not blunt the type 2 immune response to L. major (15). The difference between the two discrepant findings could be attributable to different roles of arginase between the two Leishmania spp., or to the different effects of partial vs total abrogation of arginase activity on the immune response possibly due to a more efficient attenuation of virulence in the ⌬arg mutant.…”

Section: Discussioncontrasting

confidence: 99%

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An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

Gaur¹,

Roberts

Dalvi³

et al. 2007

The Journal of Immunology

107

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Classical activation of macrophages infected with Leishmania species results in expression and activation of inducible NO synthase (iNOS) leading to intracellular parasite killing. Macrophages can contrastingly undergo alternative activation with increased arginase activity, metabolism of arginine along the polyamine pathway, and consequent parasite survival. An active role for parasite-encoded arginase in host microbicidal responses has not previously been documented. To test the hypothesis that parasite-encoded arginase can influence macrophage responses to intracellular Leishmania, a comparative genetic approach featuring arginase-deficient mutants of L. mexicana lacking both alleles of the gene encoding arginase (Δarg), as well as wild-type and complemented Δarg controls (Δarg[pArg]), was implemented. The studies showed: 1) the absence of parasite arginase resulted in a significantly attenuated infection of mice (p < 0.05); 2) poorer survival of Δarg in mouse macrophages than controls correlated with greater NO generation; 3) the difference between Δarg or control intracellular survival was abrogated in iNOS-deficient macrophages, suggesting iNOS activity was responsible for increased Δarg killing; 4) consistently, immunohistochemistry showed enhanced nitrotyrosine modifications in tissues of mice infected with Δarg compared with control parasites. Furthermore, 5) in the face of decreased parasite survival, lymph node cells draining cutaneous lesions of Δarg parasites produced more IFN-γ and less IL-4 and IL-10 than controls. These data intimate that parasite-encoded arginase of Leishmania mexicana subverts macrophage microbicidal activity by diverting arginine away from iNOS.

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Section: Discussioncontrasting

confidence: 99%

“…Ornithine is a key intermediate in the synthesis of glutamine, proline, and polyamines in mammalian cells (13). However, in Leishmania promastigotes the sole role of ornithine is the production of polyamines, which are ubiquitous essential cations that play critical roles in a variety of cellular processes needed by proliferating cells (14,15).…”

mentioning

confidence: 99%

An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

Gaur¹,

Roberts

Dalvi³

et al. 2007

The Journal of Immunology

107

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“…Arginase catalyzes the hydrolysis of L-arginine to urea and L-ornithine. L-Ornithine is used by L. major to make polyamines essential for parasite growth [42,43]. We compared the ability of Pten flox/flox and LysMCrePten flox/flox macrophages to express iNOS and produce NO after Eur.…”

Section: Impaired Ifn-c-induced No Synthesis Inos Expression and Tnfmentioning

confidence: 99%

Effective clearance of intracellular Leishmania majorin vivo requires Pten in macrophages

et al. 2008

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Leishmaniases are a major international public health problem, and macrophages are crucial for host resistance to this parasite. To determine if phosphatase and tensin homologue deleted on chromosome ten (Pten), a negative regulator of the PI3K pathway, plays a role in macrophage-mediated resistance to Leishmania, we generated C57BL/6 mice lacking Pten specifically in macrophages (LysMCrePten flox/flox mice). Examination of lesions resulting from Leishmania major infection showed that LysMCrePten flox/flox mice were more susceptible to the parasite than wild-type (WT) mice in the early phase of the infection, but were eventually able to eliminate the pathogen. In vitro Pten-deficient macrophages showed a reduced ability to kill parasites in response to IFN-c treatment, possibly because the mutant cells exhibited decreased TNF secretion that correlated with reductions in inducible nitric oxide synthase expression and nitric oxide production. In response to various TLR ligands, Pten-deficient macrophages produced less TNF and IL-12 but more IL-10 than WT cells. However, analysis of cells in the lymph nodes draining L. major inoculation sites indicated that both LysMCrePten flox/flox and WT mice developed normal Th1 responses following L. major infection, in line with the ability of LysMCrePten flox/flox mice to eventually eliminate the parasite. Our results indicate that the efficient clearance of intracellular parasites requires Pten in macrophages.Key words: Leishmania Á Macrophage Á Pten IntroductionIn humans, Leishmania infections are classified as self-healing, cutaneous, mucocutaneous or visceral [1]. These clinical manifestations of the disease reflect differences among infecting parasite species as well as the efficiency of the host's immune response to a given species. Many of the clinical manifestations of human leishmaniasis are mimicked in inbred mice, and experimental infection of various mouse strains with Leishmania major is widely used to study resistance and susceptibility to leishmaniasis. These studies have shown that intact phagocyte function is essential for recovery from Leishmania infections. In an attempt to thwart this means of host defense, Leishmania disrupt numerous Eur. J. Immunol. 2008. 38: 1331-1340 Immunity to infection , and this TNF synergizes with IFN-c to promote parasite killing [4, 5]. Mice resistant to infection with L. major have elevated levels of TNF in their draining lymph nodes (LN) during the course of the infection, whereas no TNF is detectable in susceptible animals [6]. In addition, C57BL/6 mice, which are resistant to L. major infection, become susceptible if they transgenically express high levels of the competitive inhibitor soluble hTNFRp55 fusion protein [7]. Knockout mice lacking TNFRp55 or TNF are also susceptible to this parasite [8][9][10].Signaling through both FccR [11] and TLR (especially TLR2 [12] and TLR4 [13, 14]) is known to be important for macrophagemediated defense against Leishmania. However, how these receptors are linked to TNF production is ...

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“…[8][9][10] Furthermore, host defence to Leishmania is not solely built on immune components but also relies on regulatory metabolic messengers, such as the arginine pathway intermediates. 11,12 This special liaison between immune and metabolic system has only found attention in the last few years and hence still represents a largely unexplored source of potential new information on infection mechanisms. [13][14][15] Metabolic profiling has shown great promise in discovering parasite-specific imprints on global host metabolism but has not yet been investigated with Leishmania infection in vivo.…”

Section: Introductionmentioning

confidence: 99%

Metabolic, Immune, and Gut Microbial Signals Mount a Systems Response to Leishmania major Infection

et al. 2014

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leishmaniasis in humans, a neglected tropical disease that is difficult to manage. To understand the determinants of pathology, we studied L. major infection in two mouse models: the self-healing C57BL/6 strain and the nonhealing BALB/c strain. Metabolic profiling of urine, plasma, and feces via proton NMR spectroscopy was performed to discover parasite-specific imprints on global host metabolism. Plasma cytokine status and fecal microbiome were also characterized as additional metrics of the host response to infection. Results demonstrated differences in glucose and lipid metabolism, distinctive immunological phenotypes, and shifts in microbial composition between the two models.We present a novel approach to integrate such metrics using correlation network analyses, whereby self-healing mice demonstrated an orchestrated interaction between the biological measures shortly after infection. In contrast, the response observed in nonhealing mice was delayed and fragmented. Our study suggests that trans-system communication across host metabolism, the innate immune system, and gut microbiome is key for a successful host response to L. major and provides a new concept, potentially translatable to other diseases. 4

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Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo

Cited by 256 publications

References 70 publications

An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

Effective clearance of intracellular Leishmania majorin vivo requires Pten in macrophages

Metabolic, Immune, and Gut Microbial Signals Mount a Systems Response to Leishmania major Infection

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