INNATE RESISTANCE TO EXPERIMENTAL AFRICAN TRYPANOSOMIASIS: DIFFERENCES IN CYTOKINE (TNF-α, IL-6, IL-10 AND IL-12) PRODUCTION BY BONE MARROW-DERIVED MACROPHAGES FROM RESISTANT AND SUSCEPTIBLE MICE

Kaushik, Radhey S.; Uzonna, Jude E.; Zhang, Ying; Gordon, John; Tabel, H.

doi:10.1006/cyto.2000.0685

Cited by 64 publications

(69 citation statements)

References 50 publications

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“…The present results, however, combined with the recent observation that macrophagederived TNF concentrations can also kill T. gambiense parasites in mixed cell cultures (16), suggest that local production of TNF by activated macrophages represents an efficient killing mechanisms in vivo that can explain the impairment of peak parasitemia control observed in TNFϪ/Ϫ mice (30). Furthermore, these results can be linked to reports from others that are highly suggestive for a role of local macrophage activation in early resistance toward both T. brucei (31,32) and T. congolense (33) infections. As such, local TNF production, rather than systemic serum TNF levels, should be considered FIG.…”

Section: Discussionsupporting

confidence: 76%

A Conserved Flagellar Pocket Exposed High Mannose Moiety Is Used by African Trypanosomes as a Host Cytokine Binding Molecule

Magez¹,

Radwanska²,

Stijlemans³

et al. 2001

Journal of Biological Chemistry

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Trypanosomes use antigenic variation of their variantspecific surface glycoprotein (VSG) coat as defense against the host immune system. However, in order to sustain their growth, they need to expose conserved epitopes, allowing host macromolecule binding and receptor-mediated endocytosis. Here we show that Trypanosoma brucei uses the conserved chitobiose-oligomannose (GlcNAc 2 -Man 5-9 ) moieties of its VSG as a binding ligand for tumor necrosis factor (TNF), a host cytokine with lectin-like properties. As endocytosis in trypanosomes is restricted to the flagellar pocket, we show that soluble flagellar pocket extracts, and in particular soluble VSG, inhibit the binding of 125 I-TNF to trypanosomes. The interaction between TNF and VSG is confirmed by affinity chromatography, biosensor, and dotblot affinity measurements, and soluble VSG inhibition of TNF-mediated trypanolysis. In all approaches, removal of N-linked carbohydrates abrogates the TNF-VSG interaction. In addition, synthetic high mannose oligosaccharides can block TNF-VSG interactions, and a VSG glycopeptide carrying the GlcNAc 2 -Man 5-9 moiety is shown to inhibit TNF-mediated trypanosome killing in mixed parasite/ macrophage cell cultures. Together, these results support the observation that TNF plays a role in growth control of trypanosomes and, moreover, suggest that, by the use of conserved VSG carbohydrates as lectin-binding epitopes, trypanosomes can limit the necessity to express large numbers of invariant surface exposed receptors.African trypanosomes are extracellular parasitic protozoa transmitted by tsetse flies, causing human sleeping sickness and animal infections. In order to survive, trypanosomes need to evade effective immune recognition and destruction, but also need to bind and endocytose host macromolecules via conserved surface-exposed specific receptors. Although the mechanisms of immune evasion are largely unraveled and mainly rely on antigenic variation of the parasite surface glycoprotein VSG 1 (1, 2), until now the information available on the mechanisms by which parasites can selectively take up host macromolecules has been limited (3). Indeed, the only trypanosome receptor identified so far is the ESAG 6/7-encoded transferrinbinding protein (4 -6). In contrast, the pathway of endocytosis of host macromolecules itself has been analyzed and documented extensively in case of trypanosomes. Endocytosis was shown only to occur inside the flagellar pocket of the parasite (7). This membrane region is unique in the sense that it lacks the structure of closely arranged microtubules that supports the parasite shape over the rest of the cell surface (8, 9). In bloodstream form trypanosomes, uptake of macromolecules through the flagellar pocket seems to occur via the classic pathway of coated pit formation and transport by coated vesicles to lysozyme-like organelles. This has been described for the uptake of ferritin (7) and transferrin (4), for the trypanolytic factor associated with high density lipoprotein (10), and for the inflammato...

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Section: Discussionsupporting

confidence: 76%

A Conserved Flagellar Pocket Exposed High Mannose Moiety Is Used by African Trypanosomes as a Host Cytokine Binding Molecule

Magez¹,

Radwanska²,

Stijlemans³

et al. 2001

Journal of Biological Chemistry

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“…Note how the intelectin-1 gene product is amplified in all three cases, whereas the intelectin-2 gene product is amplified from 129/SvEv and BALB/c DNA, but not that from C57BL/10 mice. differences in their ability to produce regulatory cytokines, such as IL-10, in response to infections (25). However, the fact that intelectin-2 is so markedly up-regulated in response to infection, becoming one of the most abundantly expressed proteins in infected epithelium (7), suggests that it may play an important role in the innate immune response to parasite infection.…”

Section: Discussionmentioning

confidence: 99%

Innate BALB/c Enteric Epithelial Responses to Trichinella spiralis: Inducible Expression of a Novel Goblet Cell Lectin, Intelectin-2, and Its Natural Deletion in C57BL/10 Mice

Pemberton

Knight

Gamble

et al. 2004

The Journal of Immunology

121

132

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Infection of mice with the nematode parasite Trichinella spiralis induces changes in the proteome of the jejunal epithelium, including substantial up-regulation of a novel variant of interlectin. In this study we sequence this novel lectin, termed intelectin-2, and compare expression levels during T. spiralis infection of resistant (BALB/c) with susceptible (C57BL/10) mouse strains. Intelectin-2 was cloned and sequenced from BALB/c mRNA extracted on day 14 of infection, and was found to have 91% amino acid identity with intelectin (within our study termed intelectin-1). Intelectin-2 transcripts were up-regulated early (day 3) during infection with T. spiralis in BALB/c mice, suggesting an innate response, and levels remained high through to day 14 (time of parasite rejection). Immunohistochemistry of jejunal sections with a rabbit polyclonal Ab to Xenopus laevis 35-kDa cortical granule lectin (XL35; 68% identity with intelectin-2) followed a similar pattern, with intense labeling of goblet and Paneth cells at day 14. However, intelectin-2 transcripts and protein were absent, and immunohistochemistry negative when C57BL/10 mice were infected with T. spiralis. Genomic PCR and Southern blotting confirmed that the intelectin-2 gene is absent from the C57BL/10 genome. The presence of intelectin-2 in resistant BALB/c mice, its absence from the susceptible C57BL/10 strain and the kinetics of its up-regulation during T. spiralis infection suggest that this novel lectin may serve a protective role in the innate immune response to parasite infection.

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“…with 10 3 T. congolense, BALB/c mice have a mean survival time of 8.5 Ϯ 0.5 days, whereas C57BL/6 mice survive for more than 100 days (40). Infected BALB/c mice die of systemic inflammatory response syndrome (SIRS), which is associated with high production of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-␣), interleukin-6 (IL-6), IL-12, and gamma interferon (IFN-␥) (12,37,39,40,43,45). Interestingly, blockade of IL-10 signaling either by anti-IL-10R monoclonal antibody (MAb) treatment (35,36,38) or knocking out the IL-10 gene (7) induces early death in the infected relatively resistant C57BL/6 mice.…”

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confidence: 99%

Interleukin-17-Mediated Control of Parasitemia in ExperimentalTrypanosoma congolenseInfection in Mice

et al. 2010

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BALB/c mice are highly susceptible to experimental Trypanosoma congolense infections, whereas C57BL/6 mice are relatively resistant. Infected highly susceptible BALB/c mice die of systemic inflammatory response syndrome. Because interleukin-17 (IL-17) and Th17 cells regulate inflammatory responses, we investigated their role in the pathogenesis of experimental African trypanosomiasis in mice. We show that the production of IL-17 by spleen and liver cells and the serum IL-17 level increased after T. congolense infection in mice. Interestingly, infected highly susceptible BALB/c mice produced more IL-17 and had more Th17 cells than infected relatively resistant C57BL/6 mice. Paradoxically, neutralization of IL-17 with anti-IL-17 monoclonal antibody in vivo induced higher parasitemia in both the susceptible and the relatively resistant mice. Interestingly, anti-IL-17 antibody-treated mice had higher serum levels of alanine aminotransferase and aspartate aminotransferase, and the production of IL-10 and nitric oxide by liver cells was markedly decreased. Moreover, recombinant IL-17-treated mice exhibited significantly faster parasite control and lower peak parasitemia compared to control mice. Collectively, these results suggest that the IL-17/Th17 axis plays a protective role in murine experimental African trypanosomiasis.

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INNATE RESISTANCE TO EXPERIMENTAL AFRICAN TRYPANOSOMIASIS: DIFFERENCES IN CYTOKINE (TNF-α, IL-6, IL-10 AND IL-12) PRODUCTION BY BONE MARROW-DERIVED MACROPHAGES FROM RESISTANT AND SUSCEPTIBLE MICE

Cited by 64 publications

References 50 publications

A Conserved Flagellar Pocket Exposed High Mannose Moiety Is Used by African Trypanosomes as a Host Cytokine Binding Molecule

A Conserved Flagellar Pocket Exposed High Mannose Moiety Is Used by African Trypanosomes as a Host Cytokine Binding Molecule

Innate BALB/c Enteric Epithelial Responses to Trichinella spiralis: Inducible Expression of a Novel Goblet Cell Lectin, Intelectin-2, and Its Natural Deletion in C57BL/10 Mice

Interleukin-17-Mediated Control of Parasitemia in ExperimentalTrypanosoma congolenseInfection in Mice

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