Genetic and immunological basis of human African trypanosomiasis.

Human African trypanosomiasis, or sleeping sickness, results from infection by two subspecies of the protozoan flagellate parasite Trypanosoma brucei, termed Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, prevalent in western and eastern Africa respectively. These subspecies escape the trypanolytic potential of human serum, which efficiently acts against the prototype species Trypanosoma brucei brucei, responsible for the Nagana disease in cattle. We review the various strategies and components used by trypanosomes to counteract the immune defences of their host, highlighting the adaptive genomic evolution that occurred in both parasite and host to take the lead in this battle. The main parasite surface antigen, named Variant Surface Glycoprotein or VSG, appears to play a key role in different processes involved in the dialogue with the host.

New WHO guidelines for treatment of gambiense human African trypanosomiasis including fexinidazole: substantial changes for clinical practice.

Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a parasitic infection that usually progresses to coma and death unless treated. WHO has updated its guidelines for the treatment of this infection on the basis of independent literature reviews and using the Grading of Recommendations Assessment, Development and Evaluation methodology. The first-line treatment options, pentamidine and nifurtimox-eflornithine combination therapy, have been expanded to include fexinidazole, an oral monotherapy given a positive opinion from the European Medicines Agency. Fexinidazole is recommended for individuals who are aged 6 years and older with a bodyweight of 20 kg or more, who have first-stage or second-stage gambiense human African trypanosomiasis and a cerebrospinal fluid leucocyte count less than 100 per µL. Nifurtimox-eflornithine combination therapy remains recommended for patients with 100 leucocytes per µL or more. Without clinical suspicion of severe second-stage disease, lumbar puncture can be avoided and fexinidazole can be given. Fexinidazole should only be administered under supervision of trained health staff. Because these recommendations are expected to change clinical practice considerably, health professionals should consult the detailed WHO guidelines. These guidelines will be updated as evidence accrues.

Resolving the apparent transmission paradox of African sleeping sickness.

Human African trypanosomiasis (HAT), or African sleeping sickness, is a fatal disease found throughout sub-Saharan Africa. The disease is close to elimination in many areas, although it was similarly close to elimination once before and subsequently reemerged, despite seemingly low rates of transmission. Determining how these foci persisted and overcame an apparent transmission paradox is key to finally eliminating HAT. By assessing clinical, laboratory, and mathematical data, we propose that asymptomatic infections contribute to transmission through the presence of an overlooked reservoir of skin-dwelling parasites. Our assessment suggests that a combination of asymptomatic and parasitaemic cases is sufficient to maintain transmission at foci without animal reservoirs, and we argue that the current policy not to treat asymptomatic HAT should be reconsidered.

Is there a suburban sleeping sickness in Libreville?

BACKGROUND: The transmission of sleeping sickness occurs primarily in rural areas, and exposed populations are those living from rural activities such as agriculture, fishing, animal husbandry or hunting. However, urban and suburban foci are more and more reported in T. b. gambiense areas. In Libreville town, sleeping sickness cases are regularly diagnosed. In order to investigate about the establishment of a transmission cycle of that disease, we have carried out an entomological survey in two quarters in the vicinity of the town. METHODS: Vavoua traps were set out in all suitable biotopes for tsetse flies during four days and examined twice a day. Flies were collected, identified and dissected. RESULTS: Two species of Glossina were caught: G. palpalis palpalis (90.58%) and G. caliginea (9.42%). A total infection rate of 9.37% was observed after dissection of all non-teneral flies captured. CONCLUSION: These results suggest the establishment of a trypanosomiasis transmission cycle in the area. No salivary gland was found infected. Given that infected persons are regularly detected, we can think about the existence of a suburban sleeping sickness focus in Libreville. More analysis is needed concerning the identification of human trypanosomes and the origin of Glossina blood meals that may confirm the existence of that focus.

Bactéria ou parasita? a controvérsia sobre a etiologia da doença do sono e a participação portuguesa, 1898-1904 / Bacteria or parasite? the controversy over the etiology of sleeping sickness and the Portuguese participation, 1898-1904

A etiologia da doença do sono era desconhecida até o início do século XX. Essa doença tipicamente africana em breve se tornaria o principal obstáculo à colonização europeia. O envio de missões científicas às colônias para seu estudo in loco tornou-se inevitável. Portugal enviou a primeira missão de estudo, a Angola, em 1901, e a Royal Society of London apoiou duas missões britânicas de estudo da doença, em Entebe. O resultado dessas investigações estabeleceu uma controvérsia, na qual Portugal esteve envolvido de 1898 a 1904, no circuito nacional e internacional, objeto de análise deste artigo.

The etiology of sleeping sickness was unknown until the early twentieth century. This African disease soon became the main obstacle to European colonization. Sending scientific missions to the colonies to monitor its progression in loco thus became inevitable. Portugal sent the first research mission to Angola in 1901, and the Royal Society of London sponsored two British missions to study the disease in Entebbe (1902 and 1903). Their results led to a controversy in which Portugal was involved from 1898 to 1904, on the national and international circuits, analysed in this article.

Trypanosoma brucei infection in a HIV positive Ugandan male.

Human African Trypanosomiasis, or African Sleeping Sickness, is a parasitic infection caused by Trypanosoma brucei (gambiense or rhodesiense), and one of the declared neglected tropical diseases. Sleeping sickness has high fatality rates and is a continued threat in several African countries. We present characteristic clinical and microbiologic features of a fatal case of African Sleeping Sickness in an HIV-infected individual.

Trypanosoma brucei brucei: A comparison of gene expression in the liver and spleen of infected mice utilizing cDNA microarray technology.

Trypanosoma brucei brucei, the infectious agent of the disease known as Nagana, is a pathogenic trypanosome occurring in Africa, where it causes significant economic loss to domesticated livestock. Although many studies on the histopathology of organs of mice infected with T. b. brucei have been reported, little work has been done regarding gene expression in these organs in infected mice. In this paper, we describe the use of cDNA microarray to determine gene expression profiles in the liver and spleen of mice infected with T. b. brucei (STIB 920) at peak parasitaemia (12 days after infection). Our results showed that a total of 123 genes in the liver and 389 genes in the spleen were expressed differentially in T. b. brucei infected mice. In contrast, however, in an acute infection in mice caused by Trypanosoma brucei evansi, a species genetically related to T. b. brucei, 336 genes in the liver and 190 genes in the spleen were expressed, differentially, indicating that the liver of mice was more affected by the acute T. b. evansi infection whilst the spleen was more affected by the subacute T. b. brucei infection. Our results provide a number of possible reasons why mice infected with T. b. evansi die sooner than those infected with T. b. brucei: (1) mice infected with T. b. evansi may need more stress response proteins to help them pass through the infection and these are probably excessively consumed; (2) proliferating cell nuclear antigen was more down-regulated in the liver of mice infected with T. b. evansi, which indicated that the inhibition of proliferation of hepatocytes in mice infected with T. b. evansi might be more severe than that in T. b. brucei infection; and (3) more hepatocyte apoptosis occurred in the mice infected with T. b. evansi and this might be probably the most important reason why mice died sooner than those infected with T. b. brucei. Studies of the changes in the gene expression profile in the liver and spleen of mice infected with T. b. brucei may be helpful in understanding the mechanisms of pathogenesis in Nagana disease at the molecular level. By comparing the gene profiles of the liver and spleen of mice infected with T. b. brucei with T. b. evansi, we have identified a number of factors that could explain the differences in pathogenesis in mice infected with these two African trypanosomes.

The marine sponge Diacarnus bismarckensis as a source of peroxiterpene inhibitors of Trypanosoma brucei, the causative agent of sleeping sickness.

Human African trypanosomiasis, also known as African sleeping sickness, is a neglected tropical disease with inadequate therapeutic options. We have launched a collaborative new lead discovery venture using our repository of extracts and natural product compounds as input into our growth inhibition primary screen against Trypanosoma brucei. Careful evaluation of the spectral data of the natural products and derivatives allowed for the elucidation of the absolute configuration (using the modified Mosher's method) of two new peroxiterpenes: (+)-muqubilone B (1a) and (-)-ent-muqubilone (3a). Five known compounds were also isolated: (+)-sigmosceptrellin A (4a), (+)-sigmosceptrellin A methyl ester (4b), (-)-sigmosceptrellin B (5), (+)-epi-muqubillin A (6), and (-)-epi-nuapapuin B methyl ester (7). The isolated peroxiterpenes demonstrated activities in the range IC(50) = 0.2-2 mug/mL.

Seasonal variation in human African trypanosomiasis in Tarangire National Park in Babati district, Tanzania.

A survey was carried out to determine seasonal epidemiological variation of human African trypanosomiasis (HAT) in Tarangire National Park and villages around it in Babati District, Tanzania. Concentration and Field's stain techniques were employed to examine the presence of trypanosomes in human blood samples. Tsetse flies were collected using traps and dissected under light microscope to examine for presence of trypanosomes. Retrospective data on HAT were sought from health facilities. Blood samples were collected from a total 509 individuals (306 during the dry and 203 during wet seasons). None of the individuals was infected with trypanosomes in the area. A total of 766 tsetse flies were collected. Of these, Glossina swynnertoni accounted for 94.6% and G. pallidipes for 5.4% of the total collection. The largest proportion (63.8%) of the tsetse flies was collected during the wet season. Glossina swynnertoni was most abundant tsetse species during both wet and dry seasons. Salivary gland examination revealed the presence of Trypanosoma brucei type of infection in 3.2% of tsetse flies collected. All infective trypanosomes were found during the dry season. This study concludes that the transmission and prevalence of HAT among human population in Tarangire National Pars and its surrounding villages is low despite the recent reports on tourists acquiring the infection during their visits to the Park. However, disease surveillance needs to be strengthened to monitor any impending epidemic.

Animal models of human African trypanosomiasis--very useful or too far removed?

Animal models of human African trypanosomiasis, also known as sleeping sickness, have been used for many years both to investigate disease pathogenesis and to test novel drug therapies. Model systems used have included mice, rats and non-human primates such as monkeys. Whilst such animal models have some definite but unavoidable limitations, it is argued that these are outweighed by their advantages. The latter include the ability to investigate disease pathogenesis mechanistically and the mechanisms of trypanosome traversal of the blood-brain barrier, as well as the identification of new potential drug targets and staging biomarkers, new drug therapies and combinations, and potential drug toxicity.

Sleeping sickness--a re-emerging disease in the Serengeti?

Sleeping sickness is a re-emerging disease in the Serengeti ecosystem affecting both local people and tourists. Here we report the results of a survey to assess the prevalence of trypanosomiasis in both domestic and wild animals from this area. Five hundred and eighteen cattle samples were collected from 12 villages that bordered the Serengeti National Park and 220 samples from 15 different wild animal species were collected from within the park. PCR analysis, directed against the human serum resistance associated gene SRA, identified human infective Trypanosoma brucei rhodesiense parasites in both cattle and warthogs.

Clinical follow-up in the rat experimental model of African trypanosomiasis.

Animal models of Human African Trypanosomiasis (HAT) have been developed to understand the pathogenic mechanisms leading to the passage into the neurological phase, most of them referring to histological aspects but not clinical or behavioral data. Our study aimed at defining simple clinical and/or behavioral markers of the passage between the hemolymphatic phase and the meningo-encephalitic stage of the disease. Sprague-Dawley rats (n=24) were infected with Trypanosoma brucei brucei AnTat 1.1E. Food intake and body weight were measured daily from the day of infection until death. Hematocrit was measured twice a week. Behavioral disturbances were evaluated through an Open-field test. A sudden weight loss occurred on the twelfth day after infection, due to a significant drop of food intake starting two days before. The rats developed an anemic state shown by the hematocrit measurements. The Open-field test showed them to be less active and reactive as soon as the second week after infestation. A complementary histological study observed trypanosomes and inflammatory cells in the choroid plexus at the same period. These results are in favor of central nervous system functional disturbances. The observed weight loss is discussed as being a parameter of the entry in the meningo-encephalitic phase. The rat model reproduces neurological symptoms observed in the human disease and may prove to be useful for further neurohistological and therapeutic studies.

Susceptibility of heat shock protein 70.1-deficient C57BL/6 J, wild-type C57BL/6 J and A/J mice to Trypanosoma congolense infection.

The heat shock protein (HSP) 70.1 gene lies on mouse chromosome 17 among the candidates for Tir1, the major quantitative trait locus associated with response to Trypanosoma congolense infection. To evaluate whether the HSP70.1 gene is involved in the response, we compared the susceptibility of HSP70.1-deficient C57BL/6 J, resistant wild-type C57BL/6 J and susceptible A/J mice. No differences were observed between HSP70.1-deficient and wild-type C57BL/6 J mice in survival time, levels of parasitemia and anemia, suggesting that there is no involvement of the HSP70.1 gene in control of T. congolense infection. The course of infection was markedly different between A/J and C57BL/6 J mice. A/J mice showed a bi-phasic survival pattern, which seemed to be associated with two waves of high parasitemia, but developed only moderate anemia. C57BL/6 J mice controlled parasitemia well but developed severe anemia in the late stage of infection.

African trypanosomiasis in two travelers from the United States.

African trypanosomiasis is a rare but well-documented cause of fever in United States travelers returning from areas where it is endemic. We report two recently diagnosed cases that involved tourists who went on safari in Tanzania. Review of these and 29 other published cases indicates that disease in returning United States travelers is nearly always of the East African form, a fulminant illness for which prompt diagnosis is necessary. In the United States, timely and appropriate therapy for this disease has resulted in favorable outcomes for most patients. Chemoprophylaxis for East African trypanosomiasis is not recommended, but travelers visiting areas of endemicity should practice appropriate preventive measures to prevent tsetse fly bites.

Tsetse-trypanosome interactions: rites of passage.

Trypanosomes that cause sleeping sickness (Trypanosoma brucei rhodesiense and T. b. gambiense) are entirely dependent on tsetse for their transmission between hosts, but the flies are not easily infected. This situation has not arisen by chance - the tsetse has evolved an efficient defence system against trypanosome invasion. In this review, Susan Welburn and Ian Maudlin chart the progress of trypanosomes through the fly and identify some of the hazards faced by both parasite and fly that affect vector competence of tsetse.

Susceptibility of severe combined immuno-deficient (SCID) mice to Trypanosoma brucei gambiense and T. b. rhodesiense.

Susceptibility of severe combined immunodeficient (SCID) mice to 7 isolates of Trypanosoma brucei gambiense and 2 isolates of T. b. rhodesiense was examined in terms of their infectivity, course of parasitaemia, packed cell volume (PCV) and survival period in comparison with that of normal immunocompetent (BALB/c) mice. All isolates of T. b. gambiense and T. b. rhodesiense caused high (> 1 x 10(8) parasites/ml) parasitaemia in the SCID mice, the survival periods ranged from 5 to 47 days. On the other hand, 5 of 7 isolates of T. b. gambiense developed chronic infection in the BALB/c mice with sporadic but persistent parasitaemia with less than 5 x 10(6) parasites/ml. All the mice tested in this group survived more than 60 days after infection. In contrast, the 2 remaining isolates of T. b. gambiense and both isolates of T. b. rhodesiense showed high virulence in the BALB/c mice and killed all of them within 30 days after infection. The results demonstrate that the SCID mice, in which functional B- and T-cell-mediated immunities are congenitally lacking, are highly susceptible for 'low-virulence' T. b. gambiense. This makes SCID mice useful tools for the isolation of parasites from T. b. gambiense sleeping sickness patients and the propagation of large amounts of such parasites.

Endotoxin antibodies in African sleeping sickness.

Antibodies to the core region of endotoxin (endotoxin core antibodies, EndoCAb), which cross-react with endotoxin from a range of Gram-negative bacteria, are maintained in relative homeostasis in health, but undergo marked changes in a number of different diseases associated directly or indirectly with endotoxaemic or septicaemic states. The levels of EndoCAb IgG in the blood and cerebrospinal fluid (CSF) of 35 late-stage sleeping sickness patients and 9 control individuals were measured by ELISA. EndoCAb levels were significantly elevated in the patient blood (mean EndoCAb value 290 MU/ml cf. control 182 MU/ml, P < 0.001), and CSF (mean EndoCAb value 254 MU/ml cf. control 150 MU/ml, P < 0.001). EndoCAb IgG levels correlated with endotoxin levels in patient blood (r = 0.78, P < 0.001), but not in the CSF and were not reduced 6 weeks following chemotherapy, unlike the endotoxin levels. It is concluded that late-stage sleeping sickness is associated with chronic exposure to endotoxins from Gram-negative bacteria.