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

Gaur, Upasna; Roberts, Sigrid C.; Dalvi, Rahul P.; Corraliza, Inés; Ullman, Buddy; Wilson, Mary E.

doi:10.4049/jimmunol.179.12.8446

Cited by 107 publications

(106 citation statements)

References 51 publications

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“…As far as Leishmania arginase is concerned, the lack of this enzyme as in arg À/À L. major or in arg À/À L. mexicana showed impaired infectivity resulting in delayed onset of lesion development, attenuated pathology, and low parasite burden [22]. Results also suggest that parasite-encoded arginase of L. major subverts macrophage microbicidal activity by diverting arginine away from iNOS [23]. L-arginine depletion and arginase-1-induced polyamine production favors the growth of L. major, and parasite-encoded arginase seems to partially control parasite replication and disease manifestation in macrophages [22].…”

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confidence: 63%

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

et al. 2011

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Although enhanced macrophage-specific arginase activity is directly related to increased parasite burden in cutaneous leishmaniasis (CL), the regulation and precise role of arginase in the disease outcome of visceral leishmaniasis (VL) has yet to be explored. As in CL, BALB/c mice infected with Leishmania donovani showed increased levels of arginase in acute infection. Arginase 1 is the major isoform associated with infection and while the IL-4-induced arginase pathway is operative in CL, IL-10 plays a crucial role in modulating arginase activity in VL, although a synergism with IL-4 is required. IL-10, in combination with IL-4, regulated both in vivo and ex vivo arginase 1 induction in a STAT6 and C/EBPbdependent fashion. Further investigation toward the cause of such synergism suggests that induction of a STAT3-dependent IL-10-mediated cascade in VL triggers the expression and surface localization of the IL-4 receptor alpha (IL-4Ra) which, in turn, enhances IL-4 responsiveness toward STAT6 and C/EBPb-dependent signaling for arginase 1. This could also offer a mechanistic explanation for the fact that, in spite of the low level of IL-4 in VL, enhanced IL-4-Ra expression by IL-10 might markedly amplify IL-4-mediated arginase 1 signaling and provide a possible mechanism for synergistic induction of arginase 1.Keywords: Arginase 1 . IL-4 . IL-10 . IL-4 receptor a . Visceral leishmaniasis IntroductionArginase is classically considered as a rate-limiting enzyme of the urea cycle in liver, but has been found to be present in a number of organs and tissues where the urea cycle is not operative. To date, two distinct isoforms of arginase have been identified in mammals. They are encoded by different genes differing in their cellular localization as well as their mode of regulation: type 1 arginase, a cytosolic enzyme expressed at high levels in liver, and type 2 arginase, a mitochondrial enzyme found in several tissues in addition to liver [1]. A growing body of evidence suggests that arginase induction is correlated with parasite-specific immunosuppression of host, thereby facilitating pathogen survival and growth inside the hostile environment of phagocytic cells. Macrophages were found to upregulate arginase 1 expression upon activation by Th2 cytokines and shown to have a detrimental role in parasite infection by limiting the Th1-dependent parasite clearance [2]. Interestingly, cAMP and TGFb are known to induce arginase 1 induction in macrophages [3]. In Chagas disease, induction of the arginase pathway could be used by Trypanosoma cruzi to spread inside host [4]. Arginase activity was triggered in macrophages from mice infected with the helminth Schistosoma mansoni and was associated with an increase in concentration of circulating L-ornithine-derived polyamines [5]. Intracellular pathogens like Salmonella enterica and Mycobacterium tuberculosis also utilize host arginase for their own 992survival within the macrophages [6,7]. Moreover, in bacteria like Helicobacter pyroli, arginase plays a major role in its surv...

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confidence: 63%

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

et al. 2011

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“…Whether all of these enzymes are also essential for the amastigote to maintain an infection is less clear, because virulence data with knockout strains from several species have not offered a consistent conclusion. Parasite burdens and lesion sizes of mice infected with ⌬arg L. mexicana (23) or ⌬arg L. major (43,48) were only somewhat lower than those of mice infected with the corresponding wildtype line from which these mutants were derived. In contrast, parasite loads in mice infected with ⌬odc L. donovani (12) were dramatically reduced by many orders of magnitude compared to those in mice inoculated with the wild-type progenitor.…”

Section: Discussionmentioning

confidence: 92%

“…The genes encoding all four enzymes have been cloned, and conditionally lethal gene knockouts have been created in L. mexicana and L. major (⌬arg mutant only) (23,43,48,52) and in L. donovani (⌬odc, ⌬spdsyn, and ⌬adometdc mutants) (12,34,50,51) via double-targeted gene replacement. Growth studies with the mutant promastigotes revealed that each knockout was auxotrophic for polyamines as a consequence of the gene deletion events and that this nutritional deficiency could be circumvented by propagation in medium supplemented with an appropriate source of polyamine or polyamine precursor.…”

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confidence: 99%

Spermidine Synthase Is Required for Virulence of Leishmania donovani

et al. 2011

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Genetic lesions in the polyamine biosynthetic pathway of Leishmania donovani, the causal agent of visceral leishmaniasis, are conditionally lethal mutations that render the insect vector form of the parasite auxotrophic for polyamines. Recently, we have demonstrated that a ⌬odc L. donovani null mutant lacking ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was profoundly compromised in its ability to infect mice, indicating that ODC is essential for the infectious mammalian stage of the parasite and further validating the enzyme as a possible drug target. To assess whether other components of the polyamine biosynthetic pathway were also essential for parasite virulence, a cell line deficient in spermidine synthase (SPDSYN), the enzyme that converts putrescine to spermidine, was created by double-targeted gene replacement within a virulent L. donovani background. This ⌬spdsyn strain was auxotrophic for polyamines, required spermidine for growth in its insect vector form, and was adversely impacted in its ability to infect mice. These findings establish that SPDSYN, like ODC, is essential for maintaining a robust infection in mammals and indicate that pharmacologic inhibition of SPDSYN, and perhaps all components of the polyamine biosynthetic pathway, is a valid therapeutic strategy for the treatment of visceral and, potentially, other forms of leishmaniasis.

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“…The L. mexicana knockout for arginase infection led to an enhanced Th1 response associated to an INF-γ upregulation as well. Taken together, these responses led to a significant growth attenuation of the parasite in mice (Gaur et al, 2007). Considering the importance of the cellular signaling pathways involving the host cells and parasites of the Leishmania genus there are few studies in the literature connecting the importance of the parasite arginase inhibition and macrophage NO production.…”

Section: Resultsmentioning

confidence: 99%

Antileishmanial activity of nerolidol-rich essential oil from Piper claussenianum

Marques¹,

Barreto²,

Curvelo³

et al. 2011

Rev. bras. farmacogn.

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Leishmaniasis is one of the most neglected tropical diseases, representing a group of parasitic diseases worldwide spread, occurring in 88 tropical and subtropical countries. Approximately 350 million people live in areas of active transmission of leishmaniasis, with about 1-2 million estimated new cases occurring every year. More than 90% of the cutaneous cases appear in developing countries. Efforts to improve the therapeutic arsenal against leishmaniasis have led to the search for new and cheap range of drugs. In this study, the nerolidol-rich essential oil from Piper claussenianum (Miq.) C. DC., Piperaceae, was assayed on arginase activity of Leishmania amazonensis. The effect of this essential oil on arginase activity levels showed an enzyme inhibition of 62.2%. This result stimulates the scientific interest about the potential value of this plant species on neglected diseases as potential new natural product source of pharmacological interest for the treatment of leishmaniasis.

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

Cited by 107 publications

References 51 publications

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

Spermidine Synthase Is Required for Virulence of Leishmania donovani

Antileishmanial activity of nerolidol-rich essential oil from Piper claussenianum

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