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Resistance and genetic sensitivity to sleeping sickness

16.10.2006
Human African trypanosomiasis, more commonly called sleeping sickness, is induced by a parasite, the trypanosome, transmitted to humans by the bite of an insect, the glossinid tse-tse fly.

There has been a resurgence of this disease over the past 20 years in Sub-Saharan Africa. The World Health Organization (WHO) in a 1998 report estimated the number of people infected to be about 300 000. Awareness of the seriousness of the situation led to an increase in screening and treatment operations over the past five years, allowing a substantial fall in the number of subjects infected.

Sleeping sickness classically manifests itself in two forms, corresponding to two parasite subspecies. The chronic form, encountered in Central and West African countries, is caused by Trypanosoma brucei gambiense (T.b. gambiense). Its development cycle in the host vaires greatly, from a few months to several years. The acute form of the disease is brought on by Trypanosoma brucei rhodesiense (T.b. rhodesiense), in southern and eastern African countries. The infection it induces takes effect after a few weeks. More virulent than the chronic form, its development cycle is also more rapid and, consequently, clinical detection can be made earlier.

However, it is increasingly recognized that the existence of these two forms, the chronic one due to T. b. gambiense and the acute one provoked by T. b. rhodesiense, only partly reflect the real mechanisms at work. Concerning the Gambian form, the screening and treatment teams indicates the occurrence of several categories of subjects infected: some show Glossina fuscipes gorged with blood affected by classical chronic forms of the disease; others bear severe rapidly developing forms; still other people show no symptoms of human African trypanosomiasis, in spite of a long period of infection. This diversity in host clinical presentation in reaction to infection can have several sources: the host's ability to respond to infection, the degree of parasite virulence or pathogenicity and the environment.

An IRD team focused particularly on the role of host genetic diversity in response to T. b. gambiense infection (whether or not the disease develops). As human experimentation is excluded, genetic, epidemiological and statistical methods, all brought under the term genetic epidemiology, were developed in order to identify the chromosome regions and/or DNA mutations involved in the development of the disease. The researchers used association techniques in order to determine the influence of certain mutations on the DNA of genes coding for particular immune system proteins (cytokines) in manifestation of the disease. This type of study consists in comparing the frequency of a mutation in subjects with symptoms and in healthy individuals. When the frequency of a mutation is significantly higher in the sick subjects than in the healthy ones, this mutation is associated with an enhanced risk of developing the disease. Conversely, a significantly lower frequency is an expression of a protective effect conferred by the mutation.

The two studies conducted in two distinct foci of the disease, respectively at Sinfra in the Ivory Coast and at Bandundu in the Democratic Republic of Congo (1), revealed evidence of three associations between a DNA mutation and the development of the disease. Depending on their position on certain cytokines genes, the mutations investigated were shown to be capable of inducing in the subject carrying them an increased risk of developing this human trypanosomiasis, or conversely a higher chance of a protector effect (2).

The associations brought out between these mutations and the disease necessitate work to confirm this in different populations and environments. New investigations, particularly in genetic epidemiology, are currently being put into operation in order to check up on possible effects of genetic predisposition already observed. The results obtained will help improve our knowledge about host-parasite interactions, by means of identifying genetic markers signalling risk. That should open the way in the long term to possible development of innovative control strategies against sleeping sickness.

(1) The Ivory Coast study involved 200 subjects with the disease and 302 healthy subjects. The study carried out in the Democratic Republic of Congo investigated 353 subjects including 135 suffering from the infection.

(2) (2) The Ivory Coast study suggests that the individuals carrying mutation A (substitution of a cytosine base by an adenine), located at position -592 of the gene coding for Interleukin 10, had a smaller risk of developing the disease. However, subjects carrying two alleles with mutation at position -308 of the gene coding for the Tumor Necrosis Factor-a showed an increased risk of developing this trypanosomiasis, rapidly after exposure to the risk of infection. In the subjects from the Democratic Republic of Congo, mutation T (substitution of a cytosine base by a thymine) at position 4339 of the Interleukin 6 coding gene could confer a protection against development of the disease. A tendency towards the association was also observed between mutation T at position 5417 of the gene coding for Interleukin 1a and a higher risk of developing this sleeping sickness.

Aude Sonneville (DIC)/ David Courtin - IRD

Marie Guillaume-Signoret | EurekAlert!
Further information:
http://www.ird.fr

Further reports about: Chronic Disease Genetic Infection developing gambiense sleeping trypanosomiasis

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