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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, so-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 available.
"It's like putting on a new coat," says Nina Papavasiliou, an immunologist at the German Cancer Research Center (DKFZ). Masked trypanosomes are no longer recognized by antibodies, proliferate rapidly, and the infection, which initially curbed the immune system, reappears.
"For decades, we have badumed that only the constituents of the amino acids the new VSGs are responsible for the pathogens that escape the immune system," says Erec Stebbins, also at DKFZ. "But now we have discovered that sugar molecules also play a role in making 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 X-ray structure badysis. One of the molecules, VSG3, researchers have discovered binding sites for sugar molecules on "the outside" immune system.With other research, Michael Ferguson of the University from Dundee, Scotland, discovered that these binding sites are in fact filled with a variety of different sugars.
To find out if sugar chains have an influence On parasite multiplication or immune defense success, scientists around Papavasiliou created trypanosomes with molecular-biological methods that VSG3 lacked at the 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 on VSG3 but also on 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, different sugars are an additional strategy by which parasites make it difficult the elimination of the pathogen by the immune system, "says Papavasiliou.
How exactly sugars hinder the immune system, the researchers can not yet say." 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 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 result in 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 Cancer Research Center (DKFZ ) has 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. The DKFZ is 90% funded by the Federal Ministry of Education and Research and 10% by the Land of Baden-Württemberg and is a member of the Helmholtz Association of German Research Centers.
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idw 2018/07
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