Role of host phosphotyrosine phosphatase SHP-1 in the development of murine leishmaniasis

Forget, Geneviève; Siminovitch, Katherine A.; Brochu, Sébastien; Rivest, Serge; Radzioch, Danuta; Olivier, Martin

doi:10.1002/1521-4141(200111)31:11<3185::aid-immu3185>3.0.co;2-j

Cited by 87 publications

(100 citation statements)

References 36 publications

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“…These data suggest that SHP-1 has the ability to control neutrophil recruitment, possibly via negative regulation of MIP-2. This is further supported by the fact that the higher neutrophil recruitment in footpads of viable motheaten mice in response to Lm infection [18] was accompanied by stronger MIP-2 expression (Fig. 1B).…”

Section: Tnf-a and Mip-2 Expression In Leishmania Majorinfected Footpadsmentioning

confidence: 52%

“…In a previous study [18], we observed that a greater number of cells were recruited in the Lm-infected footpads of SHP-1-deficient mice in comparison to their littermates. Knowing that the TNF-a cytokine is an important inflammatory mediator [19], recognized for its role in the modulation of cell recruitment [20] and healing of pathogen-induced lesions [21,22], it was essential to evaluate its expression in the footpads during Lm infection.…”

Section: Tnf-a and Mip-2 Expression In Leishmania Majorinfected Footpadsmentioning

confidence: 68%

“…In these latter, the signal remained high on day 3 post infection and slowly declined on day 7, whereas the amount of TNF-a mRNA returned to basal levels by day 3 in wild-type littermates. This result suggests that in the absence of SHP-1, TNF-a gene expression is enhanced during Lm infection, which could explain in part the greater number of inflammatory leukocytes observed in footpads of SHP-1-deficient mice [18].…”

Section: Tnf-a and Mip-2 Expression In Leishmania Majorinfected Footpadsmentioning

confidence: 89%

“…We previously found that the greater number of recruited neutrophils in infected footpads of SHP-1-deficient mice was responsible for controlling the infection, especially during the innate immune response [18]. The MIP-2 chemokine is recognized to attract mainly neutrophils to inflammatory sites [24].…”

Section: Tnf-a and Mip-2 Expression In Leishmania Majorinfected Footpadsmentioning

confidence: 99%

“…Using SHP-1-deficient viable motheaten mice, we were able to demonstrate that modulation of the signaling terminator SHP-1 is essential for Leishmania survival and progression of the disease [18]. This protection was related to elevated nitric oxide generation and massive neutrophilrecruitmentindeficientanimals.Inthepresent study, we were interested to identify the mechanisms whereby this protection occurs by establishing the exact early inflammatory events that occur in viable motheaten mice in response to Leishmania major (Lm) infection.…”

Section: Introductionmentioning

confidence: 95%

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Regulation of theLeishmania-induced innate inflammatory response by the protein tyrosine phosphatase SHP-1

et al. 2005

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Modulation of the phagocyte protein tyrosine phosphatase (PTP) SHP-1 by the parasite Leishmania favors its survival and propagation within its mammalian host. In vivo, the absence of SHP-1 leads to virtually absent footpad swelling, accompanied by enhanced inducible nitric oxide synthase expression. In this study, using an air pouch model, we show that viable motheaten SHP-1-deficient mice harbored a stronger inflammatory response against Leishmania infection than wild-type mice. This response was portrayed by higher pro-inflammatory cytokine (TNF-a, IL-1b and IL-6) expression and secretion and by greater chemokine and chemokine receptor expression. These inflammatory molecules were probably responsible for the stronger cellular recruitment, mainly of neutrophils, seen at the site of infection in viable motheaten mice within 6 h post inoculation. We also provide strong evidence that protein tyrosine phosphatases in general, and SHP-1 in particular, are important regulators of chemokine gene expression. Overall, this study suggests that the ability of Leishmania to induce SHP-1 activity in its host allows the taming of an otherwise strong innate inflammatory response that would be detrimental for its survival and progression.

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Section: Tnf-a and Mip-2 Expression In Leishmania Majorinfected Footpadsmentioning

confidence: 52%

Section: Tnf-a and Mip-2 Expression In Leishmania Majorinfected Footpadsmentioning

confidence: 68%

Section: Tnf-a and Mip-2 Expression In Leishmania Majorinfected Footpadsmentioning

confidence: 89%

Section: Tnf-a and Mip-2 Expression In Leishmania Majorinfected Footpadsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Regulation of theLeishmania-induced innate inflammatory response by the protein tyrosine phosphatase SHP-1

et al. 2005

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A novel form of NF‐κB is induced by Leishmania infection: Involvement in macrophage gene expression

et al. 2008

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2Leishmania spp. are obligate intracellular parasites that inhabit the phagolysosomes of macrophages. Manipulation of host cell signaling pathways and gene expression by Leishmania is critical for Leishmania's survival and resultant pathology. Here, we show that infection of macrophages with Leishmania promastigotes in vitro causes specific cleavage of the NF-jB p65RelA subunit. Cleavage occurs in the cytoplasm and is dependent on the Leishmania protease gp63. The resulting fragment, p35RelA , migrates to the nucleus, where it binds DNA as a heterodimer with NF-jB p50. Importantly, induction of chemokine gene expression (MIP-2/CXCL2, MCP-1/CCL2, MIP-1a/CCL3, MIP-1b/CCL4) by Leishmania is NF-jB dependent, which implies that p35 RelA /p50 dimers are able to activate transcription, despite the absence of a recognized transcriptional transactivation domain. NF-jB cleavage was observed following infection with a range of pathogenic species, including L. donovani, L. major, L. mexicana, and L. (Viannia) braziliensis, but not the non-pathogenic L. tarentolae or treatment with IFN-c. These results indicate a novel mechanism by which a pathogen can subvert a macrophage's regulatory pathways to alter NF-jB activity.

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Selective targeting of indel‐inferred differences in spatial structures of highly homologous proteins

2005

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Recent findings have shown that the protein elongation factor-1alpha (EF-1alpha) from the eukaryotic pathogen Leishmania donovani possesses virulence properties. This was unexpected, since it has greater than 80% sequence identity with its human homologue. Given that EF-1alpha is essential for cell survival, in principle, it can be considered an attractive drug target. However, the challenge is to be able to selectively target the protein so as not to affect function of the human homologue. While a limited number of discrete differences were scattered throughout the sequence, most of the difference between these 2 homologues could be attributed to a 12-amino acid insert present in human EF-1alpha and absent from the leishmania sequence. In the present study, we modeled the spatial differences in structures of human and L. donovani EF-1alpha's inferred by this insertion-deletion (or "indel"). The protein models were used to develop antibodies directed specifically toward the deletion region of the pathogen protein. The strategy described allowed successful selective targeting of this putative leishmania virulence factor while avoiding recognition of the highly similar human EF-1alpha homologue. These findings may establish a new strategy for the development of antagonists directed against certain pathogenic targets having close human homologues.

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Role of host phosphotyrosine phosphatase SHP-1 in the development of murine leishmaniasis

Cited by 87 publications

References 36 publications

Regulation of theLeishmania-induced innate inflammatory response by the protein tyrosine phosphatase SHP-1

Regulation of theLeishmania-induced innate inflammatory response by the protein tyrosine phosphatase SHP-1

A novel form of NF‐κB is induced by Leishmania infection: Involvement in macrophage gene expression

Selective targeting of indel‐inferred differences in spatial structures of highly homologous proteins

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