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Prions are definitely the most mysterious pathogens in the living world. Bereft of genetic matter, they are composed of a single, abnormally replicated protein which ‘recruits’ other proteins by transferring this deviant conformation. Diseases caused by prions are especially common in ruminants: cows, sheep, goats and deer. But they can also cause human diseases such as Creutzfeldt-Jakob disease, Kuru and Fatal familial insomnia.

As is the case with bacteria and viruses, there are several strains of prions. The sequencing of their component amino acids is the same, but their three-dimensional structure differs. Each strain has its own characteristics: the incubation period, virulence, symptoms triggered, and the ability to cross the species barrier varies from one strain to another. Furthermore, certain strains are better than others at infecting certain brain regions or cell populations. So while some prions can infect non-nervous tissue, such as lymphatic tissue, others cannot.

Currently, it is unknown why activity differs depending on the cells infected. It is one of the questions that INRA teams are trying to answer. To study the problem, they created several transgenic mouse lines with ovine PrP protein expression. Prions target this protein, and change its conformation upon contact with the pathogen. Once its structure has been modified, it accumulates in brain cells, with fatal consequences. The mouse lines were designed so that PrP expression levels differed in each line. As a result, PrP concentration in certain lines was similar to that found in a healthy animal, while in the others, levels were ten times higher.

The researchers then infected these mice with a sample taken from a sheep with scrapie (a prion-caused disease). This isolate was found to contain several prion strains. Results show that certain strains were more often found in mouse lines with high levels of PrP, and less common in lines with a low concentration of this protein. Therefore, the virulence of each strain varies depending on the quantity of substrate present.

This new finding raises another question: is the ‘preference’ of certain strains for certain brain cells the result of PrP concentration levels in these cells? If so, the research has identified a potential factor in the increase or slowdown of prion activity. It will also shed light on the question of how prion strains naturally evolve, on which INRA teams will now focus their research.

Reference

Annick Le Dur, Thanh Lan Laï, Marie-George Stinnakre, Aude Laisné, Nathalie Chenais, Sabine Rakotobe, Bruno Passet, Fabienne Reine, Solange Soulier, Laetitia Herzog, Gaëlle Tilly, Human Rézaei, Vincent Béringue, Jean-Luc Vilotte, Hubert Laude, Divergent prion strain evolution driven by PrPC expression level in transgenic mice. ¶Nature Communications. 14170