Human African trypanosomiasis & heart.

INTRODUCTION: Human African Trypanosomiasis is a neglected tropical disease resulting from the infection with the parasite Trypanosoma brucei. Neurological compromise often dominates, and the impact of cardiovascular involvement has not been fully investigated. Recently, publications indicate that cardiovascular compromise is more frequent than previously thought. Early detection of cardiac complications may be of utmost importance for healthcare teams. AREA COVERED: As a part of the 'Neglected Tropical Diseases and other Infectious Diseases involving the Heart' (the NET-Heart Project), the purpose of this article is to review all the information available regarding cardiovascular implications of this disease, focusing on diagnosis and treatment, and proposing strategies for early detection of cardiac manifestations. An electronic systematic literature review of articles published in MEDLINE, PubMed and EMBASE was performed. From 50 initial studies, 18 were selected according to inclusion criteria. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was used for conducting and reporting this review. EXPERT OPINION: Cardiovascular compromise through infiltrative and inflammatory mechanisms seems to be frequent, and includes a wide spectrum of severity. Conventional 12-lead electrocardiogram could be a useful test for screening cardiovascular manifestations and used as a guide for considering specific treatments or more sophisticated diagnostic tools.

Cardiac manifestations of parasitic diseases.

The heart may be affected directly or indirectly by a variety of protozoa and helminths. This involvement may manifest in different ways, but the syndromes resulting from impairment of the myocardium and pericardium are the most frequent. The myocardium may be invaded by parasites that trigger local inflammatory response with subsequent myocarditis or cardiomyopathy, as occurs in Chagas disease, African trypanosomiasis, toxoplasmosis, trichinellosis and infection with free-living amoebae. In amoebiasis and echinococcosis, the pericardium is the structure most frequently involved with consequent pericardial effusion, acute pericarditis, cardiac tamponade or constrictive pericarditis. Chronic hypereosinophilia due to helminth infections, especially filarial infections, has been associated with the development of tropical endomyocardial fibrosis, a severe form of restrictive cardiomyopathy. Schistosomiasis-associated lung vasculature involvement may cause pulmonary hypertension (PH) and cor pulmonale Tropical pulmonary eosinophilia, which is characterised by progressive interstitial fibrosis and restrictive lung disease, may lead to PH and its consequences may occur in the course of filarial infections. Intracardiac rupture of an Echinococcus cyst can cause membrane or secondary cysts embolisation to the lungs or organs supplied by the systemic circulation. Although unusual causes of cardiac disease outside the endemic areas, heart involvement by parasites should be considered in the differential diagnosis especially of myocardial and/or pericardial diseases of unknown aetiology in both immunocompetent and immunocompromised individuals. In this review, we updated and summarised the current knowledge on the major heart diseases caused by protozoan and metazoan parasites, which either involve the heart directly or otherwise influence the heart adversely.

GMP synthase is essential for viability and infectivity of Trypanosoma brucei despite a redundant purine salvage pathway.

The causative agent of human African trypanosomiasis, Trypanosoma brucei, lacks de novo purine biosynthesis and depends on purine salvage from the host. The purine salvage pathway is redundant and contains two routes to guanosine-5'-monophosphate (GMP) formation: conversion from xanthosine-5'-monophosphate (XMP) by GMP synthase (GMPS) or direct salvage of guanine by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). We show recombinant T. brucei GMPS efficiently catalyzes GMP formation. Genetic knockout of GMPS in bloodstream parasites led to depletion of guanine nucleotide pools and was lethal. Growth of gmps null cells was only rescued by supraphysiological guanine concentrations (100 µM) or by expression of an extrachromosomal copy of GMPS. Hypoxanthine was a competitive inhibitor of guanine rescue, consistent with a common uptake/metabolic conversion mechanism. In mice, gmps null parasites were unable to establish an infection demonstrating that GMPS is essential for virulence and that plasma guanine is insufficient to support parasite purine requirements. These data validate GMPS as a potential therapeutic target for treatment of human African trypanosomiasis. The ability to strategically inhibit key metabolic enzymes in the purine pathway unexpectedly bypasses its functional redundancy by exploiting both the nature of pathway flux and the limited nutrient environment of the parasite's extracellular niche.

The central role of macrophages in trypanosomiasis-associated anemia: rationale for therapeutical approaches.

Bovine African trypanosomiasis causes severe economical problems on the African continent and one of the most prominent immunopathological parameters associated with this parasitic infection is anemia. In this report we review the current knowledge of the mechanisms underlying trypanosomiasis-associated anemia. In first instance, the central role of macrophages and particularly their activation state in determining the outcome of the disease (i.e. trypanosusceptibility versus trypanotolerance) will be discussed. In essence, while persistence of classically activated macrophages (M1) contributes to anemia development, switching towards alternatively activated macrophages (M2) alleviates pathology including anemia. Secondly, while parasite-derived glycolipids such as the glycosylphosphatidylinositol (GPI) induce M1, host-derived IL-10 blocks M1-mediated inflammation, promotes M2 development and prevents anemia development. In this context, strategies aimed at inducing the M1 to M2 switch, such as GPI-based treatment, adenoviral delivery of IL-10 and induction of IL-10 producing regulatory T cells will be discussed. Finally, the crucial role of iron-homeostasis in trypanosomiasis-associated anemia development will be documented to stress the analogy with anemia of chronic disease (ACD), hereby providing new insight that might contribute to the treatment of ACD.

Contributions of experimental mouse models to the understanding of African trypanosomiasis.

African trypanosomiasis is the collective name for a wide variety of trypanosome infections that affect humans and livestock. In recent years, experimental mice infection models have provided new insights into both human and animal trypanosomiasis. Mouse models seem to be a valuable and versatile tool in trypanosomiasis-associated pathology and immunology research and highlight the variety shown by African trypanosomiases. Indeed, inbred mouse strains have enabled the study of genetic determinants of susceptibility and of the roles of anti-parasite antibodies, inflammatory mediators and anti-inflammatory mediators for each trypanosome species. Remarkable advances relating to the encephalitic stage of sleeping sickness have also been achieved thanks to murine models. The different contributions of murine models to the African trypanosomiases knowledge are presented here. Future search directions are finally proposed, with respect to mouse model opportunities and limitations.

A glycosylphosphatidylinositol-based treatment alleviates trypanosomiasis-associated immunopathology.

The GPI-anchored trypanosome variant surface glycoprotein (VSG) triggers macrophages to produce TNF, involved in trypanosomiasis-associated inflammation and the clinical manifestation of sleeping sickness. Aiming at inhibiting immunopathology during experimental Trypanosoma brucei infections, a VSG-derived GPI-based treatment approach was developed. To achieve this, mice were exposed to the GPI before an infectious trypanosome challenge. This GPI-based strategy resulted in a significant prolonged survival and a substantial protection against infection-associated weight loss, liver damage, acidosis, and anemia; the latter was shown to be Ab-independent and correlated with reduced macrophage-mediated RBC clearance. In addition, GPI-based treatment resulted in reduced circulating serum levels of the inflammatory cytokines TNF and IL-6, abrogation of infection-induced LPS hypersensitivity, and an increase in circulating IL-10. At the level of trypanosomiasis-associated macrophage activation, the GPI-based treatment resulted in an impaired secretion of TNF by VSG and LPS pulsed macrophages, a reduced expression of the inflammatory cytokine genes TNF, IL-6, and IL-12, and an increased expression of the anti-inflammatory cytokine gene IL-10. In addition, this change in cytokine pattern upon GPI-based treatment was associated with the expression of alternatively activated macrophage markers. Finally, the GPI-based treatment also reduced the infection-associated pathology in Trypanosoma congolense and Trypanosoma evansi model systems as well as in tsetse fly challenge experiments, indicating potential field applicability for this intervention strategy.

Expression, purification, characterization, and in vivo targeting of trypanosome CTP synthetase for treatment of African sleeping sickness.

African sleeping sickness is a fatal disease caused by two parasite subspecies: Trypanosoma brucei gambiense and T. b. rhodesiense. We previously reported that trypanosomes have extraordinary low CTP pools compared with mammalian cells. Trypanosomes also lack salvage of cytidine/cytosine making the parasite CTP synthetase a potential target for treatment of the disease. In this study, we have expressed and purified recombinant T. brucei CTP synthetase. The enzyme has a higher K(m) value for UTP than the mammalian CTP synthetase, which in combination with a lower UTP pool may account for the low CTP pool in trypanosomes. The activity of the trypanosome CTP synthetase is irreversibly inhibited by the glutamine analogue acivicin, a drug extensively tested as an antitumor agent. There is a rapid uptake of acivicin in mice both given intraperitoneally and orally by gavage. Daily injection of acivicin in trypanosome-infected mice suppressed the infection up to one month without any significant loss of weight. Experiments with cultured bloodstream T. brucei showed that acivicin is trypanocidal if present at 1 mum concentration for at least 4 days. Therefore, acivicin may qualify as a drug with "desirable" properties, i.e. cure within 7 days, according to the current Target Product Profiles of WHO and DNDi.

[Sleeping sickness, a reemerging sickness]. / La maladie du sommeil, maladie reémergente.

Human African Trypanosomiasis (THA) has reappeared in most intertropical countries of Black Africa and an estimated 400,000 new cases are reported every year. Genetic tests which now make possible the differentiation of morphologically similar trypanosome subspecies showed that a large variety of game and domestic animals act as reservoir hosts of Trypanosoma brucei gambiense, thus making it even more difficult to fight the disease. The detection of cases and their treatment are absolutely necessary in preventing the spread of the disease. This can only be carried out with mobile medical teams which seek out patients. This detection currently calls on techniques which isolate trypanosomes and serological techniques. The collection of data with regards to different geographical positions, makes it possible to determine exactly which regions are affected, possibly affected or sound. Although the diagnosis of the hemo-lymphatic stage can be determined without any great problem nowadays, the point at which the trypanosome invades CNS tissues and the ways in which it occurs are as yet unknown, even though the role of nitric oxyde and cytokines is better understood. Antibodies, anti-neurofilaments and anti-galactocerebrosides when found in the cerebro-spinal fluid are characteristic of the nervous stage of the disease. This condition is really sleeping sickness, not only hypersomnia. The more seriously the patient is affected the shorter the sleep-wake cycles are during the nycthemeron. These early disorders can be quickly reversed thanks to therapy, which to day uses melarsoprol, an arsenical drug, which cannot be of great promise as it is very toxic. Current research into nitro-imidazole derivatives (particularly megazol) seems a promising therapy as they were effective in vitro and in vivo, in rodents and primates.

Neurobiology of cerebral malaria and African sleeping sickness.

This review is aimed at emphasizing the need for basic neuroscience research on two tropical diseases, malaria and sleeping sickness (African trypanosomiasis), that still represent major health problems and in which severe involvement of the nervous system is frequently the direct cause of death. The life cycles of the two parasites, the protozoan Plasmodium and Trypanosoma brucei, which are the causative agents of malaria and sleeping sickness, respectively, are briefly reviewed. The historical contribution to the pathogenesis and therapy of malaria by a renowned pioneer in neuroscience, Camillo Golgi, is pointed out. The different strategies for survival in the host by the intracellular Plasmodium and the extracellular African trypanosomes are summarized; such strategies include sites favorable for hiding or replication of the parasites in the host, antigenic variation, and interactions with the cytokine network of the host. In particular, tumor necrosis factor-alpha and interferon-gamma may play a role in these infections. The parasites may paradoxically interact with cytokines to their benefit. However, cytokine receptors are expressed on neuronal subsets sensitive to cytokine action, and stimulation of these subsets may cause neuronal dysfunctions during the infections. Finally, the clinical symptoms of cerebral malaria and African trypanosomiasis and research aiming at deciphering their pathogenetic mechanisms that could affect the nervous system at a molecular level are described. The need for neuroscientists in this endeavor is emphasized.

Cytotoxicity of monoclonal antibodies to Trypanosoma brucei.

Monoclonal antibodies (McAbs) were raised against Metacyclic Variable Antigen Types (M-VATs) of the AnTAR 1 and ETAR 1 serodemes of Trypanosoma brucei. Two dominant M-VATs, one from each serodeme, were labelled by two of the McAbs using the indirect immunofluorescence technique. These McAbs were of the IgM class, and labelled exposed epitopes on living trypanosomes. They showed lytic activity in vitro towards their respective homologous VAT trypanosomes, both in the presence and absence of complement. In vivo, the McAbs promoted lysis and clearance of trypanosomes from the bloodstream of infected mice. Prevention of reinfection with trypanosomes expressing the same VAT was conferred by the McAbs.