Endotoxins in the blood and cerebrospinal fluid of patients with African sleeping sickness

Pentreath, V. W.; Alafiatayo, Ruth; Crawley, B.; Doua, F.; Oppenheim, E

doi:10.1017/s0031182000065082

Cited by 49 publications

(23 citation statements)

References 15 publications

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“…Some of these agents, such as VSG and trypanosome DNA, originate from the parasite; others will originate from the host, such as IFN-γ. The levels of circulating LPS also increase during African trypanosomiasis (30,31,29). This increase is likely because of an increase in gut permeability (45) and it is thought that this increase in LPS contributes to the pathology of the disease by increasing the proinflammatory environment of the host (30-32).…”

Section: Discussionmentioning

confidence: 99%

“…LPS is a Gramnegative bacterial product and the agonist for Toll-like receptor 4 (TLR4). LPS is also relevant during a natural T. brucei infection, because levels of circulating LPS are increased in both experimental and human African trypanosomiasis (29)(30)(31) and it is thought that this LPS contributes to pathology in trypanosomiasis by increasing the proinflammatory environment of the host (31,32). The alteration in glycolytic rate (which is HIF-1α-dependent) in murine bone marrow-derived macrophages (BMDM), following LPS stimulation was examined.…”

Section: Indolepyruvate Alters the Glycolytic State Of The Cell Follomentioning

confidence: 99%

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Trypanosoma bruceimetabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The parasite Trypanasoma brucei causes African trypanosomiasis, known as sleeping sickness in humans and nagana in domestic animals. These diseases are a major burden in the 36 sub-Saharan African countries where the tsetse fly vector is endemic. Untreated trypanosomiasis is fatal and the current treatments are stagedependent and can be problematic during the meningoencephalitic stage, where no new therapies have been developed in recent years and the current drugs have a low therapeutic index. There is a need for more effective treatments and a better understanding of how these parasites evade the host immune response will help in this regard. The bloodstream form of T. brucei excretes significant amounts of aromatic ketoacids, including indolepyruvate, a transamination product of tryptophan. This study demonstrates that this process is essential in bloodstream forms, is mediated by a specialized isoform of cytoplasmic aminotransferase and, importantly, reveals an immunomodulatory role for indolepyruvate. Indolepyruvate prevents the LPS-induced glycolytic shift in macrophages. This effect is the result of an increase in the hydroxylation and degradation of the transcription factor hypoxia-inducible factor-1α (HIF-1α). The reduction in HIF-1α levels by indolepyruvate, following LPS or trypanosome activation, results in a decrease in production of the proinflammatory cytokine IL-1β. These data demonstrate an important role for indolepyruvate in immune evasion by T. brucei.immunometabolism | innate immunity | immune evasion |

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Section: Discussionmentioning

confidence: 99%

Section: Indolepyruvate Alters the Glycolytic State Of The Cell Follomentioning

confidence: 99%

Trypanosoma bruceimetabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Arginase I is induced by Th2 cytokines in bone marrow-derived macrophages (28). Endotoxin and circulating Th1 and Th2 cytokine levels are increased in trypanosomiasis (1,32,33). Ϫ concentrations were assayed in each supernatant (gray bars).…”

Section: Discussionmentioning

confidence: 99%

l-Arginine Availability Modulates Local Nitric Oxide Production and Parasite Killing in Experimental Trypanosomiasis

et al. 2000

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Nitric oxide (NO) is an important effector molecule of the immune system in eliminating numerous pathogens. Peritoneal macrophages fromTrypanosoma brucei brucei-infected mice express type II NO synthase (NOS-II), produce NO, and kill parasites in the presence ofl-arginine in vitro. Nevertheless, parasites proliferate in the vicinity of these macrophages in vivo. The present study shows thatl-arginine availability modulates NO production. Trypanosomes use l-arginine for polyamine synthesis, required for DNA and trypanothione synthesis. Moreover, arginase activity is up-regulated in macrophages from infected mice from the first days of infection. Arginase competes with NOS-II for their common substrate, l-arginine. In vitro, arginase inhibitors decreased urea production, increased macrophage nitrite production, and restored trypanosome killing. In vivo, a dramatic decrease inl-arginine concentration was observed in plasma from infected mice. In situ restoration of NO production and trypanosome killing were observed when excess l-arginine, but notd-arginine or l-arginine plusN ω-nitro-l-arginine (a NOS inhibitor), was injected into the peritoneum of infected mice. These data indicate the role of l-arginine depletion, induced by arginase and parasites, in modulating the l-arginine–NO pathway under pathophysiological conditions.

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“…T. bruceiinfected mice became extremely sensitive to LPS hypersensitivity [9], which is relevant because LPS serum levels increase during the infection, both in human and experimental mouse infections [31,32]. Consequently, low-dose LPS-induced mortality was analyzed.…”

Section: Development Of Pathology In T Brucei Parasitemiamentioning

confidence: 99%

P75 Tumor Necrosis Factor–Receptor Shedding Occurs as a Protective Host Response during African Trypanosomiasis

Truyens²,

et al. 2004

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In experimental murine trypanosomiasis, resistance is often scored as the capacity to control peak parasitemia levels, which results in prolonged survival. Infection-induced pathology has not systematically been used as a resistance criterion. Because this parameter could be the most relevant for comparative analysis of natural and experimental infections, as well as for understanding of pathology-associated immune alterations, we analyzed Trypanosoma brucei infections in 4 different established conventional mouse models, as well as in tumor necrosis factor (TNF)-deficient and TNF-receptor-deficient mice. Results indicate the following: (1) there is no correlation between peak parasitemia control or survival and the induction of infection-associated anemia, loss of body weight, liver pathology, reduced locomotor activity, and general morbidity; (2) serum levels of TNF, interferon- gamma, and interleukin-10, which are known to affect survival, do not correlate with induction of pathology; and (3) infection-induced occurrence of lipopolysaccharide hypersensitivity does not correlate with survival. However, one parameter that was found to correlate with the inhibition of trypanosomiasis-associated pathology in all models was the shedding of soluble p75 TNF-receptor during peak parasitemia stages. These results are important for future cytokine and trypanosomiasis pathology studies, because the interplay between TNF and the soluble receptors it sheds has not been considered in either human clinical sleeping sickness studies or in veterinary trypanosomiasis research.

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Endotoxins in the blood and cerebrospinal fluid of patients with African sleeping sickness

Cited by 49 publications

References 15 publications

Trypanosoma bruceimetabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion

Trypanosoma bruceimetabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion

l-Arginine Availability Modulates Local Nitric Oxide Production and Parasite Killing in Experimental Trypanosomiasis

P75 Tumor Necrosis Factor–Receptor Shedding Occurs as a Protective Host Response during African Trypanosomiasis

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