Institutions of RICET Carlos III Health Institute Biological Research Centre Ramon y Cajal Hospital López Neyra Parasitology and Biomedicine Institute Severa Ochoa Molecular Biology Centre, Autónoma University of Madrid La Laguna University Léon University Murcia University Salamanca University Valencia University

Sleeping Sickness

Manager: Miguel Ángel Navarro Carretero IPBLN-D

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Subprogram: Diagnosis, Monitoring and Control of Sleeping Sickness

Manager: Agustín Benito LLanes. ISCIII-A

Human African trypanosomiasis (HAT) is a major re-emerging human parasitosis, with increasing incidence in many regions of sub-Saharan Africa. In terms of both diagnosis and treatment, HAT is a clear example of a neglected disease, since the available serological test is somewhat unspecific and the drugs available are highly toxic.

The disease, caused by trypanosomatidae protozoa and transmitted by the tsetse fly (gen. Glossina) displays two forms, namely, Tripanosoma Brucei Gambiense and T.b. Rhodesiense. The former disease causes from 300,000 to 500,000 infections annually, mainly in the Democratic Republic of the Congo, which has the highest number of cases, followed by Angola with around 100,000 cases.

T.B. Gambiense causes sleeping disease in its chronic form, as a slow, progressive form of the disease. Without medical treatment, this disease is lethal and the development of an effective vaccine is hindered by antigenic variation of the glycoprotein on the surface of the parasite (variable surface glycoprotein - VSG). Due both to the different symptomatology of and drug sensitivity to T.b. Rhodesiense and Gambiense, along with the fact that the drugs available are effective in only some stages of the disease, swift diagnosis of HAT is of the essence. Humans are the reservoir of the disease and their treatment interrupts disease transmission, with this appearing as the only manner of controlling the infection. Nowadays, the card agglutination test for trypanosomiasis (CATT) is the only method available for serological diagnosis of HAT, since visualisation of the parasite in blood, lymp node fluid or cerebrospinal fluid by microscopy only detects 30% to 70% of cases. Furthermore, due to the high rates of trypanosomatic animals, which could be circulating between these reservoirs and humans, and whose VSGs possess antigenic cross-reactive regions, new diagnostic techniques applicable to the field must be developed.

One of the problems that are being detected in the use of the CATT as a diagnostic test in Equatorial Guinea is the high proportion of serologically positive individuals; based on this method, serologies of 1/8 or higher are assumed to be positive. This generates major doubts, since these individuals should presumably be treated in a way that entails a high degree of aggressiveness with existing treatment. In addition, in studies submitted for publication by our group, we have postulated a hypothesis, based on a study of reservoirs where we observed a very high proportion of trypanosomatidae (T. vivax, T.congolense) circulating in animal reservoirs which could be yielding serological results cross-reactive with T.b. Gambiense. Finally, PCR diagnosis for detecting the parasite in human samples will enable the result of diagnosis expressed by agglutination technique to be confirmed.

Goal

To develop sensitive and specific HAT diagnostic techniques

Subprogram: Sleeping Sickness Therapeutics

Manager: Miguel Ángel Navarro Carretero IPBLN-D

The existing drugs for combating HAT were identified in the first half of the 20th century and all display great toxicity, so that there is an evident need for new drugs to developed. Furthermore, the drugs available vary in effectiveness, depending both on the species and the stage of the disease. The disease manifests different stages, namely: the initial stages of latency, and invasion of the vascular system; and finally the period of invasion of the central nervous system, and cerebral coma.

Pentamidine, though it possesses medium toxicity, is not effective against T.b. Rhodesiense, and when the species cannot be confirmed, Suramin, which is much more toxic, tends to be used. However, neither of these drugs is effective in the late stages of the disease when the parasite invades the central nervous system (CNS), owing to the fact that they are unable to breach the blood-brain barrier. In this stage of the disease, only Melarsoprol is available, which is the most toxic of all and can lead to irreversible damage to the CNS in 10% of patients treated.

This means that, in order to find a solution to this serious situation, research on new therapeutic targets is essential.