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The new form of trypanosomiasis discovered in India stems from a deficiency in a particular immune-system protein

22.01.2007
The two known types of human trypanosomiasis, endemic in two regions of the world, are sleeping sickness in Africa, caused by the parasites Trypanosoma brucei gambiense or T. b. rhodiense, and Chagas’ disease in South America induced by T. cruzi.

Everywhere else, normally only animals are infected by trypanosomes that, although specific for humans are not pathogenic for them. Yet, in 2004, the first case of human trypanosomiasis was formally identified in India by IRD researcher Philippe Truc, working with the WHO and the Maharashtra State Department of Health (1).

The patient was a farmer living in this State who proved to be infected by a trypanosome, T. evansi, usually a parasite of camels and cattle. In South America, North Africa and in a great part of Asia including India, where this parasite is present, many human populations are currently living in contact with infected animals.

Scientists from the Université Libre de Bruxelles led by Professor Etienne Pays, in conjunction with Philippe Truc and Indian medical specialists, under an agreement with WHO (2), carried out analyses on blood serum from the infected patient, which led them to identify the cause of this first case of human trypanosomiasis in India.

Humans possess natural resistance to this parasite, as they have towards related African trypanosomes, like T. brucei. In the latter case, the innate immunity results from the trypanolytic activity of a specific human protein, apolipoprotein L-1 (APOL-1). Once absorbed inside the parasite, this protein forms pores in the parasite’s organelle membrane, thus inducing the destruction of the trypanosome. However, the two subspecies T. brucei rhodesiense and T. b. gambiense have, with time, overcome human immune defences by acquiring resistance to APOL-1 and thereby causing sleeping sickness in Africa. In T. b. rhodesiense, this resistance mechanism involves a protein that is peculiar to this subspecies, named SRA (Serum Resistance-associated protein), which interacts strongly and specifically with APOL -1, effectively blocking its ability to destroy the trypanosomes.

The major question is whether the first case of T. evansi infection identified in India resulted from the appearance of a mechanism of resistance of this parasite or from a deficiency of the patient’s immune system., The gene coding for the SRA protein, specific to the subspecies rhodesiense, was not detected in the trypanosome that had infected the Indian patient, as could be expected considering its specificity (3).

The researchers then assessed in vitro the ability of the infected serum to destroy the parasites. In this way they brought into evidence a complete absence of any trypanolytic activity on two strains of T. evansi, but also on T. b. brucei. Conversely, these same strains were destroyed on contact with normal serum. The APOL-1 protein, responsible for the trypanolytic action against T. b. brucei, was subsequently looked for in the infected serum. This serum appeared to be extremely deficient in this protein, with a concentration in APOL-1 at least 125 times lower than in normal human serum. However, the addition of a normal quantity of purified APOL-1 to the infected serum was sufficient to restore the latter’s ability to destroy the different strains tested. This APOL-1 deficiency observed in the patient would clearly therefore be the source of the single case of T. evansi infection identified to date.

Analysis of the apoL-1 gene sequence, perfomred on the patient’s DNA, showed that the absence of apolipoprotein results from a double mutation affecting its synthesis (4). In the absence of APOL-1, no other component of the human serum seems capable of forming pores in the parasite membrane and killing the trypanosome.

Furthermore, a serological screening, conducted in 2005 by the Indian authorities in the patient’s village, with the IRD researcher and assigned by WHO, brought to light an intense exposure of individuals to T. evansi, probably favoured by transmission of the parasite from infected animals to humans, via an insect vector. In fact, out of 1806 people examined, 60 proved to be strongly positive to the specific serological test for this trypanosome, although no parasite was detected in these subjects, and no case of infection has since been recorded in the village (5).

However, only study of the frequency of each of the two mutations within exposed populations will allow assessment of the risk of the appearance of other cases and the emergence of this new form of trypanosomiasis.

Marie Guillaume-Signoret – IRD
Translation : Nicholas Flay
(1) See scientific sheet n°230, August-September 2005, accessible at:
www.ird.fr/fr/actualites/fiches/2005/fiche230.htm
(2) This research was conducted by scientists from the ‘Laboratoire de Parasitologie Moléculaire (IBMM)’ of the Université Libre de Bruxelles (Belgium), jointly with a researcher from IRD research unit UR 177, medical specialists from the Department of Medicine of the Government Medical College of Nagpur (India), from the Department of Health at Mumbai (India) and from the WHO (Geneva, Switzerland).

(3) Philippe Truc et al. - Genetic characterization of Trypanosoma evansi isolated from a patient in India, Infection, Genetics and Evolution, 24 August 2006. doi:10.1016/j.meegid.2006.07.004

(4) This occurs in the form of two mutations each of which affects an allele of the same gene apoL-1. The first consists of the absence of two nucleotide bases in position 142, the second is the absence one particular base at position 266. These “frameshift” mutations result in the production of proteins that are cut down in length, and therefore ineffective. And these products are undetectable, as they are probably degraded.

(5) This means that these individuals have been or are still carriers of anti-T. evansi antibodies. They have therefore been carriers of the parasite, no doubt owing to an insufficiency in APOL-1 (mutation of a single allele?). See the reference under “For further information”.

Marie Guillaume | alfa
Further information:
http://www.ird.fr/fr/actualites/fiches/2007/fas256.pdf

Further reports about: APOL-1 INDIA Serum Who absence brucei evansi parasite trypanosome trypanosomiasis

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