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Deutsches Krebsforschungszentrum (DKFZ)
Sleep Disease – It has long been known that pathogens elude sleep sickness by replacing their Surface proteins by the immune system But now scientists have found in the Deutsches Krebsforschungszentrum an additional strategy of parasites to escape the immune system: they confuse the immune system with sugar. The sugar chains of the envelope protein prevent the binding of protective antibodies and thus increase the pathogenic properties of unicellular pathogens.
African trypanosomes, agents responsible for sleeping sickness, are known for their ability to escape the immune system. The trick with which they escape the complete destruction by the defense cells has been known for decades.
Unicellular parasites are covered by a dense layer of identical proteins, called VSGs (variable surface glycoproteins). The antibodies of the infected human are directed against these proteins, and the parasites are thus largely eliminated. But sometimes individual pathogens completely change their surface protein. To do this, they simply switch to another VSG gene – they have a thousand different ones.
"It's like putting on a new coat," says Nina Papavasiliou, an immunologist at the German Cancer Research Center (DKFZ). The trypanosomes thus masked are no longer recognized by the antibodies, they multiply rapidly, and the infection, which initially allowed to slow down the immune system, reappears.
"For decades, we have badumed that only the new VSGs are responsible for the pathogens that escape the immune system," says Erec Stebbins, also at DKFZ. "But now we've discovered that the molecules of sugar also play a role and make it even more difficult for the body's immune system to cope with the parasite. "
Stebbins and his team have now studied various VSGs by badyzing the structure of X-rays. One of the molecules, VSG3, the researchers found binding sites for sugar molecules on "the outside" immune system face.Michael Ferguson, of the University of Dundee, Scotland, discovered that these binding sites are actually filled with different sugars.
To know if sugar chains influence the multiplication of parasites or the success of the immune system Scientists around Papavasiliou developed trypanosomes with molecular biology methods that lacked VSG3's sugar binding site. While mice infected with normal trypanosomes died rapidly from infection, the animals survived infection with "sugar-free" trypanosomes and were able to completely eliminate the virus from their blood after several days.
Inoculated with trypanosomes without sugar a protective immune response. However, transmission of pathogens with normal and sweet VSG did not trigger vaccination. The researchers found the binding sites for sugar not only to VSG3 but also to many other VSGs.
"VSG sugar chains do not completely block the immune system, but they clearly prevent it In addition to switching to new VSGs, the different sugars are an additional strategy by which parasites make it difficult Elimination of the pathogen by the immune system, "explains Papavasiliou.
How do sugars hinder the defense system? Ie." They can partially obscure antibody binding sites, "speculates Stebbins, pointing out that Altered sugar molecules can also influence the immune defense of cancer cells: "Sugar molecules are very important recognition structures for the immune system. This applies to the defense against microorganisms as well as for the immune defense of tumors. "
Trypanosoma brucei, the causative agent of African sleeping sickness, is found mainly in West and Central Africa.The tsetse transmitted pathogen attacks the Central nervous system and causes serious neurological disorders Without treatment, the infection can lead to death.The number of reported cases has recently dropped from 28,000 to 2,800 patients by 90% between 1999 and 2015 (source: Médecins sans Frontières)
Jason Pinger, Dragana Nešić, Liaqat Ali, Francisco Aresta-Branco, Mirjana Lilic, Shanin Chowdhury, Kim Hee-Sook, Joseph Verdi, Jayne badr, Michael AJ Ferguson, F. Nina Papavasiliou and C. Erec Stebbins: African trypanosomes escape immune clearance by O-glycosylation of VSG surface layer
Nature Microbiology 2018, DOI: 10.1038 / s41564-018-0187
The German Center for Cancer Research (DKFZ) more Like 3,000 employees, the largest biomedical research institution in Germany. At DKFZ, more than 1,000 scientists are studying how cancer is developing, identifying cancer risk factors, and researching new strategies to prevent cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more effectively. The staff of the Cancer Information Service (KID) informs concerned individuals, interested citizens and expert groups about generalized cancer of the disease. In collaboration with the Heidelberg University Hospital, DKFZ has set up the Heidelberg National Tumor Disease Center (NCT), in which promising approaches to cancer research are transferred to the clinic. In the German consortium for translational cancer research (DKTK), one of six German health research centers, DKFZ runs translation centers in seven partner institutions. The combination of excellent academic medicine with the advanced research of a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is 90% funded by the Federal Ministry of Education and Research and 10% by the state of Baden-Württemberg and is a member of the Helmholtz Association of German Research Centers
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