TRYPANOSOMIASIS. AFRICAN TRYPANOSOMIASIS: HUMAN.
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Allergy and Immunology↗
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Trypanosomiasis. African trypanosomiasis.
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Animals↗
Selective primary health care: strategies for control of disease in the developing world. VIII. African trypanosomiasis.
African trypanosomiasis in humans is caused by trypanosomes, parasitic protozoa that inhabit the blood and tissue spaces. Humans are infected by the bite of the tsetse (Glossina species), which itself acquires the parasites from human or animal hosts. The vector and the disease are confined to sub-saharan Africa where the disease occurs in endemic foci from which epidemics arise. Two forms of African trypanosomiasis in humans are recognized and both are fatal if left untreated. Control strategy is dependent on the capacity of the public health services to diagnose and treat cases, and the maintenance of surveillance is essential if epidemics are to be prevented. In epidemics this strategy should be extended to include vector-control measures to break transmission of the disease while cases continue to be diagnosed and treated. Eradication of the vector is not feasible nor can animal reservoirs be eliminated. National authorities must thus maintain surveillance to reduce the human reservoir of infection in order for low levels of endemicity, particularly in areas where epidemics have occurred in the past, to be retained.
Developing Countries↗
Chemokines are produced in the brain early during the course of experimental African trypanosomiasis.
African trypanosomiasis is characterized by progressive central nervous system (CNS) involvement. Using single and double immunohistochemistry, we evaluated the induction of alpha- and beta-chemokines in brains of Sprague-Dawley rats infected with Trypanosoma brucei brucei (T. b. brucei) and identified their cellular source. The results showed high production of MIP-2, RANTES and MIP-1alpha and to a lower extend MCP-1 in infected animals compared to controls. MIP-2, RANTES and MIP-1alpha were produced early by astrocytes and microglia and later by macrophages and T-cells. These findings suggest that chemokines may contribute to the immunopathogenesis that occurs in the CNS early during infections.
Animals↗
Macrophages as primary target cells and mediators of immune dysfunction in African trypanosomiasis.
African trypanosomiasis is accompanied by profound general immunosuppression. The experiments described here were designed to characterize the contribution of macrophages to the immune pathology of this disease. We used peptone-stimulated, uninfected mice and injected them intraperitoneally with lethally irradiated and 35S-labeled Trypanosoma brucei and parasite-specific antisera. Peritoneal macrophages were thus induced to take up in vivo a defined number of trypanosomes. After the phagocytosis of parasites, macrophages were transferred into uninfected syngeneic mice, where they mimicked some of the important immunological changes normally associated with active trypanosome infection: (i) splenic background plaque-forming cells increased nonspecifically and (ii) the specific immune response to sheep erythrocytes was either enhanced or suppressed, depending on the timing of the antigen challenge: priming simultaneously with the transfer of trypanosome-containing macrophages enhanced immune responsiveness; in contrast, if parasite-containing macrophages were transferred and recipient mice were primed 4 days later, the immune response was suppressed. A contribution of suppressor T cells was ruled out by the treatment of peritoneal exudate cells with anti-Thy 1.2 and complement before transfer into recipient mice. The results indicate that macrophages are key cells in the mediation of parasite-induced immune dysfunction.
Animals↗
Macrophage activation in murine African trypanosomiasis.
African trypanosomiasis is accompanied by a profound general immunosuppression in which both suppressive T cells and macrophages (M phi) have been implicated. The present studies define changes in the M phi surface, endocytic and secretory properties, during the infection of mice by Trypanosoma brucei. Peritoneal M phi obtained after the control of the first wave of parasitemia displayed characteristics similar to those activated by intracellular pathogens, such as Mycobacterium bovis bacillus Calmette-Guérin, e.g., the enhanced expression of Ia antigen, decreased M phi-specific antigens, receptors mediating the pinocytosis of mannose-terminal glycoproteins, and an increased ability to secrete plasminogen activator, superoxide anion, and H2O2. Some markers of macrophage activation persisted during the subpatent period before the recurrence of parasitemia, whereas others reverted to normal. Mature T cell function appears not to be essential for M phi activation by T. brucei since the infection of athymic nude mice also induced Ia antigens and plasminogen activator. These studies show that M phi activated by different pathways express common features which may contribute to immune dysfunction observed in trypanosomiasis, as well as in other infections.
Animals↗
Production of interferons during experimental African trypanosomiasis.
African trypanosomiasis is associated with profound changes in the function of the immune system. In this study we find that alpha/beta and gamma interferon (IFN) are released into the serum of mice infected with Trypanosoma brucei. The parasite-induced rise in serum IFNs is associated with a detectable parasitaemia, but the serum IFN peak precedes the peak parasitaemia in some cases. Unlike other protozoan interferon inducers, no parasite-dependent IFN production was observed in the pre-patent period of infection; while the most virulent clone induced very high IFN levels, no clear difference in stimulation was noted in the first waves of semi-acute and chronic T. brucei clones. However, subsequent IFN augmentation more closely reflected the host parasite load and virulence of infection. The nature of the stimulatory parasite component is as yet unknown, and the parasite surface glycoprotein had no effect on serum IFN. Injection of large quantities of lethally irradiated, but intact organisms did not stimulate IFN production; however this treatment significantly impaired antibody responses to the heterologous antigen SRBC. This suggests that the more severe effects of an actual trypanosome infection are required for induction of IFN synthesis, and that the presence of measurable serum IFN is not a prerequisite for parasite-induced suppression of host antibody responses.
Animals↗
Current situation of African trypanosomiasis.
African trypanosomiasis (sleeping sickness) is fatal, if untreated, and occurs in 36 African countries, south of the Sahara, where some 50 million people are at risk of acquiring infection. In the absence of adequate control measures epidemics occur, which are costly and difficult to control. The history of sleeping sickness has been characterized by waves of epidemics, resurgences and outbreaks. Nevertheless, sleeping sickness has been brought practically under control in the early 1950s, in West and Central Africa, through systematic surveillance of the population at risk and in East Africa, mainly by vector control. Following the attainment of independence from colonial rule in subsequent years, failure by national health authorities to give due attention to sleeping sickness control, due to civil and political unrest, lack of adequate resources and competing national health priorities, has resulted in epidemics and the recrudescence of many old foci and the appearance of new ones. Thus, sleeping sickness is currently a major concern among many countries, particularly in East and Central Africa. During the past decade, progress has been achieved through research in the development of new tools for diagnosis, which are simple to use by national health personnel and for vector control, which can be used at the community level. Eflornithine, a new drug, has been registered for the treatment of gambiense sleeping sickness, and although it is expensive, it is relatively safe and provides an alternative therapy to the existing treatment, which may cause severe adverse effects. These tools have raised hopes for improved control, but their integration into health care systems, which could improve surveillance of the population at risk, has been slow. In view of the worsening economic situation of endemic countries, and the focus of attention and resources on the AIDS pandemic, prospects of any significant improvement in the sleeping sickness situation would largely depend on the successful mobilization of external resources.
Africa↗
Orchitis as an unusual manifestation of human African trypanosomiasis.
African trypanosomiasis is a re-emerging disease. We report the case of an African patient whose predominant symptom was infertility due to a granulomatous orchitis. The patient was afebrile and had not been in Africa for years. Lymphadenopathy and splenomegaly led us eventually to the diagnosis of sleeping sickness. After treatment with suramin his spermiogram returned to normal. Sleeping sickness evolves through clinically different stages and leads to death if left untreated. The disease may, however, present clinically extremely variable and may thus be difficult to diagnose.
Adult↗
Sleeping sickness: perspectives in African trypanosomiasis.
African trypanosomiasis has recently been relegated in the league table of the major infectious diseases. However, in the light of the serious instability of most countries on the African continent, due to civil unrest, political turmoil and unabated fratricidal wars, mass movements of refugees across national borders, to and from sleeping sickness foci, the resurgence and spread of this disease is on the increase. These movements of people en masse are analogous to those which, at the turn of the century led to outbreaks of sleeping sickness killing thousands of people in areas which had previously not experienced this disease. The present situation is compounded by severe budgetary constraints and lack of human resources, making it virtually impossible to undertake surveillance programmes and to deliver health services to already destabilished populations. Current molecular and biochemical studies on the African trypanosome suggest a need for reappraisal of strategies for the diagnosis and treatment of both the chronic and acute forms of sleeping sickness. These studies have also highlighted the complexity of animal trypanosomiasis (nagana). There is an urgent need to understand first, fundamental elements of protection by the immune system, especially in the light of recent findings on the interaction(s), at the outset, between T-cell subsets, B cells, cytokines and parasites and/or parasite derived components (trypanokines), and second, the mechanisms of action of the drugs currently used.
Africa↗
Perspectives in research on and control of African trypanosomiasis.
African trypanosomiasis affects both man and his domestic animals, and is fatal if untreated. The risk of epidemics makes the disease a major public health problem in 36 sub-Saharan African countries, where some 50 million people are at risk of contracting the disease. Continued suppression of the disease through medical surveillance is indispensable to prevent epidemics which are difficult and costly to control. Recent epidemics and flare-ups have occurred in certain countries due to breakdown in medical surveillance occasioned by political, social and economic factors. The development of new tools through research over the last decade has improved the diagnosis of patients and vector control. The development of eflornithine (DFMO) for the treatment of gambiense sleeping sickness is a major breakthrough in view of its safety compared with current treatment alternatives, and it has been nicknamed the 'resurrection drug'. In spite of these achievements, however, there is no radical solution to the problem of sleeping sickness. The use by the endemic countries of improved tools for disease control depends upon the availability of resources from national, bilateral and multilateral sources, and commitment of the countries concerned.
Africa↗
Analysis of macrophage activation in African trypanosomiasis.
African trypanosomes cause a fatal disease of man and animals that is characterized by extensive functional, histological, and pathological changes in the lymphoid tissues of infected hosts, including an increase in the numbers and activation state of macrophages. Macrophage activation during infection is the result of exposure of these cells to parasite components and host-derived IFN-gamma, produced in response to parasite antigens. The balance of these different activation signals may determine the outcome of infection. In the experiments described here, we assessed the ability of the variant surface glycoprotein (VSG) of the organism Trypanosoma brucei rhodesiense (T.b. rhodesiense) to activate macrophages directly. Our results demonstrate that macrophages bind and are activated by the VSG molecule. The resulting profile of activation differs from that stimulated by IFN-gamma. These results suggest that the interaction of host macrophages with VSG released during parasite infection may be a key component of trypanosomiasis.
Animals↗
Blood-brain barrier damage in experimental African trypanosomiasis.
African sleeping sickness is characterized by progressive central nervous system (CNS) involvement, leading to the so-called secondary or late stage in which there are widespread inflammatory changes with lymphoplasmocytic infiltration. A study was made of blood-brain barrier (BBB) integrity in the late stages of a rodent model by assessing the uptake of the fluorescent fluid-phase marker sulphorhodamine B into the brain tissue. Brain oedema was estimated from brain weight, density and electrolyte concentrations. Trypanosome distribution was studied by light and electron microscopy. At 35 days post-infection (p.i.) fluorescent dye penetration occurred in several brain regions, including thalamus and hypothalamus. At 40 days p.i., BBB damage was extensive, with dye penetration throughout both the grey and the white matter of the cortex. Infected rats had significantly higher brain water content than uninfected controls and altered sodium and potassium concentrations characteristic of vasogenic oedema. The morphological studies showed early accumulation of parasites within, and associated damage to the choroid plexus, and, in the late stages, the presence of small numbers of trypansomes scattered in the nerve tissue of the brain and spinal cord, similar to previous descriptions. The findings show that chronic trypanosomiasis in the rat model is accompanied by BBB damage and vasogenic oedema.
Animals↗
Regulation of innate and acquired immunity in African trypanosomiasis.
African trypanosomes are well known for their ability to avoid immune elimination by switching the immunodominant variant surface glycoprotein (VSG) coat during infection. However, antigenic variation is only one of several means by which trypanosomes manipulate the immune system of their hosts. In this article, the role of parasite factors such as GPI anchor residues of the shed VSG molecule and the release of CpG DNA, in addition to host factors such as IFN-gamma, in regulating key aspects of innate and acquired immunity during infection is examined. The biological relevance of these immunoregulatory events is discussed in the context of host and parasite survival.
Animals↗
Impairment of adrenocortical function associated with increased plasma tumor necrosis factor-alpha and interleukin-6 concentrations in African trypanosomiasis.
African sleeping sickness (SS) is a severe, potentially lethal parasitic disease. The treatments of choice are the antiparasitic agents suramin, which is adrenotoxic, and/or melarsoprol. We evaluated the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis of patients with SS before, during, and after therapy with suramin and/or melarsoprol, in two sequential stages. First, we employed the standard adrenocorticotropic hormone (ACTH) 1-24 stimulation test (250 micrograms i.v.) to assess the maximal adrenocortical responsiveness of 69 patients with SS and 38 normal controls. We demonstrated paradoxically subnormal cortisol responses before suramin therapy [net cortisol response 60 min after stimulation: 10.5 +/- 2.9 (mean +/- SE) vs. 17.5 +/- 1.0 micrograms/dl for controls, p = 0.004], with 27% of the patients falling within the adrenal insufficiency range (stimulated cortisol concentration < 20 micrograms/dl). These responses subsequently and unexpectedly improved with suramin and/or melarsoprol therapy. Second, we performed a human corticotropin-releasing hormone (hCRH) test (100 micrograms i.v.) in 68 additional patients with SS and 14 control subjects to examine whether the glucocorticoid deficiency observed was primary and/or secondary. Compared to controls, the ACTH and cortisol responses to hCRH were blunted (ACTH after 60 min: 29 +/- 7 vs. 58 +/- 8 pg/ml in controls, p = 0.014; cortisol: 15.2 +/- 1.5 vs. 19.6 +/- 0.7 micrograms/dl, p = 0.018), suggesting the presence of secondary adrenal insufficiency. There was improvement of both ACTH and cortisol responsiveness to hCRH with therapy, with cortisol recovery occurring before ACTH, suggesting an additional primary component of adrenal dysfunction in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Pathology of human African trypanosomiasis with reference to experimental African trypanosomiasis and infections of the central nervous system.
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Animals↗
Diagnostic and neuropathogenesis issues in human African trypanosomiasis.
Human African trypanosomiasis, also known as sleeping sickness, is caused by protozoan parasites of the genus Trypanosoma, and is a major cause of human mortality and morbidity. The East African and West African variants, caused by Trypanosma brucei rhodesiense and Trypanosoma brucei gambiense, respectively, differ in their presentation but the disease is fatal if untreated. Accurate staging of the disease into the early haemolymphatic stage and the late encephalitic stage is critical as the treatment for the two stages is different. The only effective drug for late stage disease, melarsoprol, which crosses the blood-brain barrier, is followed by a severe post-treatment reactive encephalopathy in 10% of cases of which half die. There is no current consensus on the diagnostic criteria for CNS involvement and the specific indications for melarsoprol therapy also differ. There is a pressing need for a quick, simple, cheap and reliable diagnostic test to diagnose Human African trypanosomiasis in the field and also to determine CNS invasion. Cerebrospinal fluid and plasma analyses in patients with Human African trypanosomiasis have indicated a role for both pro-inflammatory and counter-inflammatory cytokines in determining the severity of the meningoencephalitis of late stage disease, and, at least in T. b. rhodesiense infection, the balance of these opposing cytokines may be critical. Rodent models of Human African trypanosomiasis have proved very useful in modelling the post-treatment reactive encephalopathy of humans and have demonstrated the central role of astrocyte activation and cytokine balances in determining CNS disease. Such animal models have also allowed a greater understanding of the more direct mechanisms of trypanosome infection on CNS function including the disruption of circadian rhythms, as well as the immunological determinants of passage of trypanosomes across the blood-brain barrier.
Animals↗
Circulating antibodies directed against tryptophan-like epitopes in sera of patients with human African trypanosomiasis.
Human African trypanosomiasis is often associated with an intense proliferation of B lymphocytes, leading to polyclonal antibody synthesis. Using a modified enzyme-linked immunosorbent assay method, we have found highly significant levels of circulating anti-conjugated tryptophan-like epitope antibodies in sera of patients with sleeping sickness. These antibodies were immunoglobulins (Ig) of the M isotype. There was no correlation between immunologic binding and the Ig levels found in sera of patients with human African trypanosomiasis. Higher antibody levels in stage II of the disease than in stage I may be related to damage to the central nervous system. The specificity of this immunologic binding was evaluated by 1) comparison with that obtained with other related conjugates and 2) serum titration. Anti-conjugated tryptophan-like epitope antibodies were not found in other neurologic diseases tested. Their involvement in this pathology remains unknown.
Adolescent↗