Biologically active products from African Trypanosomes.

Tizard, Ian R.; Nielsen, K H; Seed, John; Hall, James Edwin

doi:10.1128/mmbr.42.4.664-681.1978

Cited by 69 publications

(28 citation statements)

References 106 publications

(150 reference statements)

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“…Our data suggest that the most plausible hypothesis explaining the reduced antigen presentation capacity of pMF-I is interference with the intracellular loading of antigenic peptides onto MHC class II molecules during the late stage processing of exogenous proteins as described during Leishmania or Mycobacterium infection (Pancholi et al 1993, Kima et al 1996. Such interference may result from the release of biologically active factors from living trypanosomes, impairing the vesicular traf®c within macrophages from infected animals (Tizard et al 1978, Leyva-Cobian & Unanue 1988, Kima et al 1996. Moreover, poorly degradable T. b. brucei components, such as phospholipids, could impede the encounter between MHC class II molecules and the processed peptides leading to the expression of empty MHC class II molecules on antigen presenting cell surface from infected mice (Leyva-Cobian & Unanue 1988).…”

Section: Discussionmentioning

confidence: 83%

Trypanosoma brucei brucei infection impairs MHC class II antigen presentation capacity of macrophages

Namangala

Brys

Magez

et al. 2000

Parasite Immunology

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During African trypanosomiasis, macrophages play a central role in T cell hyporesponsiveness to parasite-related and unrelated antigens. In this study, the ability of macrophages from Trypanosoma b. brucei-infected mice to present exogenous antigens to a major histocompatibility complex (MHC) class II-restricted CD4+ T cell hybridoma was analysed. We demonstrate that the antigen presentation capacity of macrophages from infected mice is markedly reduced as a result of a lower expression of [MHC class II-peptide] complexes on their plasma membrane. This defect did not result from a decreased antigen uptake/catabolism, a reduced MHC class II and intercellular adhesion molecule 1 expression on the surface of macrophages, a decreased affinity of MHC class II molecules for antigenic peptides, a competition between exogenous and parasite antigens, or the generation of inhibitory peptides. Our data indicate that the step resulting in coexpression of processed antigens and MHC class II molecules is affected in T. b. brucei-infected mice. Additionally, macrophages from infected mice secreted IL-10 that in turn contributes to the impairment of T cell activation.

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Section: Discussionmentioning

confidence: 83%

Trypanosoma brucei brucei infection impairs MHC class II antigen presentation capacity of macrophages

Namangala

Brys

Magez

et al. 2000

Parasite Immunology

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“…The demonstration here that the enzyme is able to cleave native neurotensin and atrial natriuretic factor, which have diverse roles in the complex mechanisms of control over bodily functions, means that this enzyme has the potential to seriously disrupt control mechanisms of the host system. Symptoms of sleeping sickness are difficult to define in general terms, but altered blood volume, and eventual disruption of neurological systems, is not inconsistent with the general symptoms found (Tizard et al? 1978) ; thus inappropriate cleavage of regulatory molecules by OP-Tb may have profound implications for the host.…”

Section: Hydrolysis Of Peptides By Op-tb Op-tb Successfully Cleavedmentioning

confidence: 99%

Proteases from Trypanosoma brucei brucei

Troeberg

Pike

Morty

et al. 1996

European Journal of Biochemistry

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African trypanosomes contain proteases that may be released into the bloodstream of their infected hosts. This paper describes a novel, combined isolation of a cysteine proteinase (called trypanopain-Tb) and a serine oligopeptidase (which we call oligopeptidase-Tb) from Trypanosoma brucei brucei, as well as a comparison of the activities of these two enzymes against several host regulatory molecules.The enzymes differed in various respects. Firstly, purified trypanopain-Tb was shown to readily cleave proteins such as gelatin maximally at acidic pH. In contrast, oligopeptidase-Tb, which is optimally active at alkaline pH, did not hydrolyse proteins larger than 4 kDa. However, it readily hydrolysed various polypeptides, including neurotensin and atrial natriuretic factor.The interaction of the two enzymes with mammalian protease inhibitors also differed. Cystatins and a,-macroglobulin effectively inhibited trypanopain-Tb, with the K, values for cystatin C and low-molecular-mass kininogen (-1O-~" M) predicting that trypanopain-Tb is likely to be effectively controlled by these inhibitors if released into the host bloodstream. In contrast, oligopeptidase-Tb was not inhibited by serpins or a,-macroglobulin, suggesting that it may remain active if released into the host bloodstream. In support of these in v i t m results, the blood of trypanosome-infected rats displayed no trypanopain-Tblike activity, but exhibited high oligopeptidase-Tb-like activity. Thus, while trypanopain-Tb seems likely to be confined to an intracellular role within the parasite, oligopeptidase-Tb has the potential to remain active in the host bloodstream and so contribute directly to pathogenesis.

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“…African trypanosomes of the genus Trypanosoma cause widespread disease in humans and livestock throughout sub-Saharan Africa [1]. Infection causes severe febrile illness characterized by dyspnoea, oedema, cardiomyopathy and endocrine dysfunction [2]. The pathogenic mechanisms underlying the development of these lesions have not been elucidated, but are often attributed to biologically active products released by trypanosomes into the host circulation [2].…”

Section: Introductionmentioning

confidence: 99%

Pyroglutamyl peptidase type I from Trypanosoma brucei: a new virulence factor from African trypanosomes that de-blocks regulatory peptides in the plasma of infected hosts

Morty

Bulau

Pellé

et al. 2006

Biochemical Journal

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Peptidases of parasitic protozoans are emerging as novel virulence factors and therapeutic targets in parasitic infections. A trypanosome-derived aminopeptidase that exclusively hydrolysed substrates with Glp (pyroglutamic acid) in P1 was purified 9248-fold from the plasma of rats infected with Trypanosoma brucei brucei. The enzyme responsible was cloned from a T. brucei brucei genomic DNA library and identified as type I PGP (pyroglutamyl peptidase), belonging to the C15 family of cysteine peptidases. We showed that PGP is expressed in all life cycle stages of T. brucei brucei and is expressed in four other blood-stream-form African trypanosomes. Trypanosome PGP was optimally active and stable at bloodstream pH, and was insensitive to host plasma cysteine peptidase inhibitors. Native purified and recombinant hyper-expressed trypanosome PGP removed the N-terminal Glp blocking groups from TRH (thyrotrophin-releasing hormone) and GnRH (gonadotropin-releasing hormone) with a k(cat)/K(m) value of 0.5 and 0.1 s(-1) x microM(-1) respectively. The half-life of TRH and GnRH was dramatically reduced in the plasma of trypanosome-infected rats, both in vitro and in vivo. Employing an activity-neutralizing anti-trypanosome PGP antibody, and pyroglutamyl diazomethyl ketone, a specific inhibitor of type I PGP, we demonstrated that trypanosome PGP is entirely responsible for the reduced plasma half-life of TRH, and partially responsible for the reduced plasma half-life of GnRH in a rodent model of African trypanosomiasis. The abnormal degradation of TRH and GnRH, and perhaps other neuropeptides N-terminally blocked with a pyroglutamyl moiety, by trypanosome PGP, may contribute to some of the endocrine lesions observed in African trypanosomiasis.

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Biologically active products from African Trypanosomes.

Cited by 69 publications

References 106 publications

Trypanosoma brucei brucei infection impairs MHC class II antigen presentation capacity of macrophages

Trypanosoma brucei brucei infection impairs MHC class II antigen presentation capacity of macrophages

Proteases from Trypanosoma brucei brucei

Pyroglutamyl peptidase type I from Trypanosoma brucei: a new virulence factor from African trypanosomes that de-blocks regulatory peptides in the plasma of infected hosts

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