Sleeping sickness

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7,000 new cases of sleeping sickness, each year.

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Cause

Sleeping sickness occurs when the parasite Trypanosoma brucei gambiense (West Africa) or Trypanosoma brucei rhodesiense (East Africa) is introduced into the body following a bite by a tsetse fly that had itself become infected by biting humans or animals harboring the parasite.

Tsetse flies are found only in sub-Saharan Africa, and only some species transmit the parasite. Male and female tsetse flies feed exclusively on blood – on average every three days – and act as a vector for transmitting the parasite to humans and livestock.

Trypanosome transmission is restricted to specific ecological foci. Sleeping sickness does not occur in all the areas inhabited by tsetse flies, possibly because of the complexity of parasite development in tsetse flies and the relatively low rate of infection, even in endemic areas.

Symptoms

During the first stage of the disease, the parasites in the bloodstream cause a range of general symptoms that make it hard to diagnose, such as fever, headaches, tiredness and inflammation of the lymph nodes. If the disease remains untreated, the parasites infect the central nervous system, and it is during this second stage that characteristics of the sleep/wake cycle appear. This deterioration of the central nervous system is invariably fatal if left untreated.

The parasite can also be transmitted from mother to child during pregnancy if the trypanosome crosses the placental barrier and infects the fetus.

98% of sleeping sickness cases are caused by Trypanosoma brucei gambiense, which results in chronic infection – sufferers can be infected for several months or even years without exhibiting excessively severe symptoms. When symptoms are eventually linked with the disease, it is often already at an advanced stage and the central nervous system is already affected.

Epidemiology

There have been several sleeping sickness epidemics in Africa: in 1900, 1920, and most recently an epidemic which ended in the late 1990s.

The prevalence of the disease currently varies from one region to the next, although more than 85% of reported cases since 2015 have been in the Democratic Republic of the Congo. Some countries have reported no cases for more than a decade.

Sustained efforts have led to a reduction in the number of cases since 2009. In 2017, about 1,500 cases have been identified, but the actual number of cases is estimated at more than 10,000. Social instability and/or lack of access make it hard to establish an accurate overview of the situation.

70 million people are at risk of sleeping sickness in 25 sub-Saharan African countries.

Treatment

The type of treatment depends on how advanced the disease is, but the earlier the diagnosis, the better the prognosis.

The drugs used during the first stage – pentamidine for Trypanosoma brucei gambiense and suramin for pour Trypanosoma brucei rhodesiense – have few side effects and are relatively easy to administer.

Treatment in the second stage is more complex and the drugs are more toxic as they have to cross the blood-brain barrier. Melarsoprol (derived from arsenic) is effective against Trypanosoma brucei rhodesiense but kills 5% of patients from encephalopathy. The combination of nifurtimox and eflornithine is effective and recommended for chronic forms of Trypanosoma brucei gambiense. However, this treatment is very expensive and complex to set up in the field. Fexinidazole, a short, simple and effective short oral therapy, is expected to rapidly supplant all current treatments for Trypanosoma brucei gambiense.

At the Institut Pasteur

In the Institut Pasteur’s Department of Parasites and Insect Vector, novel experimental models and tools are being developed to shed light on the dynamic interactions between these microorganisms and their hosts with the aim of identifying the fundamental principles of parasitism and vector transmission, revealing host invasion mechanisms and determining the virulence factors, pathology and survival strategies of these organisms.

The Trypanosome Cell Biology Unit, directed by Philippe Bastin, focuses entirely on the analysis of this parasitic flagellate. Two subjects of study are developed, one in parasitology and the other in cell biology. Through their research on flagella, scientists have demonstrated how vital this organelle is to the parasite as it is responsible for movement, morphogenesis and cell division. The team has recently uncovered the molecular composition of the flagellum and pinpointed several proteins in the parasite that represent targets for diagnosis and the development of new drugs. The scientists have also identified the assembly mechanism of flagella. Since 2012, the unit has been rearing tsetse flies to reproduce natural infection conditions, which has led to a range of projects aimed at understanding the early stages of infection. This information is vital for detection and rapid treatment in the field. Trypanosomes have also become a preferred model for research into ciliopathies, genetic disorders caused by defects involving cilia and flagella.

The Trypanosome Transmission Group, led by Brice Rotureau, is studying different aspects of the cyclical development of parasites in the tsetse fly, in particular their motility, sensory perception and metabolism, with the prospect of being able, for example, to block the development of parasite in the vector. The group also investigates the different stages of infection in the mammalian host after the infective bite to determine the mechanisms of differentiation, proliferation and migration of parasites occurring during the disease; this with the aim of developing new approaches for diagnosis and treatment. In particular, the presence of large amounts of parasites in the skin of patients and people free of symptoms has recently been highlighted by the group, in collaboration with researchers from the University of Kinshasa, Guinea's national control program, from the University of Glasgow and the IRD. Until now, the detection of this disease was exclusively based on the search for parasites in the blood, so researchers are now working on a non-invasive detection system of parasites hidden in the skin to identify also healthy carriers.

Finally, trypanosomes have become a first-rate model for studying eyelashes and flagella, antennae found on the surface of most cells. Some are motionless and serve to detect signals, while others are mobile and responsible for the movement of the cell or its environment. Disturbances in their functioning cause severe diseases called ciliopathies. It is a family of very debilitating genetic diseases that affect the development and functioning of certain organs, especially the brain, kidney or eyes. Since trypanosomes can be easily manipulated in the laboratory, the team dissects the flagellum assembly method using state-of-the-art techniques in genetics, optical microscopy and electron microscopy. In collaboration with several clinical teams, the team exploits the trypanosome to study the impact of genetic mutations observed in patients.

The 5-year group Trypanosome Molecular Biology, led by Lucy Glover, is interested in the regulation of gene expression, in particular the control of antigenic variation. In the infected mammal, the surface of the trypanosome is covered with a dense layer of nearly 10 million of the same surface glycoprotein, called VSG for Variant Surface Glycoprotein, easily detectable by the immune system. In order to escape the immune response of the host, T. brucei has developed a survival strategy, called antigenic variation, to continuously modify this surface antigen. It is the result of a mechanism of genetic recombination and controlled DNA repair that allows expression of a single VSG variant and concomitant inactivation of other VSG genes. It is these molecular mechanisms of genetic recombination and DNA repair that are studied in the laboratory.

 The Clinical Investigation and Access to Biological Resources platform (ICAReB), led by Marie-Noëlle Ungeheuer, establishes and manages collections of biological resources of human origin, dedicated to research teams from the Institut Pasteur but also from the international scientific community. Specialized in infectious fields and immunology, since 2008 she has played the role of WHO biobank for sleeping sickness. Its main purpose is to promote the improvement of the diagnosis of this parasitosis. More than 38,000 samples from nearly 1880 donors are available. Using data and 3500 tubes distributed to a dozen requesting laboratories, a new immunological diagnostic test (for infection) and a stage 2 biomarker, neurological, for the disease (neopterin in the cerebrospinal fluid ) were recently developed.


Statistics and data: WHO


December 2018



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