A new study shows how pathogens control changes in their cell surface to evade the immune system.
A new study by LMU and Helmholtz Munich shows how pathogens control changes in their cell surface to evade the immune system. The immune system responds to an infection by producing antibodies that recognize and bind to the cell surface of the pathogen, thus marking it as an intruder and triggering an immune response.
For this to work, the antibodies produced must exactly fit the membrane molecules of the pathogen, like a key fitting a lock. Many pathogens evade the host's immune response by periodically changing their surface antigens so that existing antibodies no longer recognize them."This strategy is known as antigenic variation," explains physicist Maria Colomé-Tatché, who is Professor of Functional Genomics and Cell Biology at LMU's Biomedical Center and leader of the Computational Epigenomics research group at Helmholtz Munich."Antigenic variation is evident in a wide range of evolutionarily distant pathogens," adds Professor Nicolai Siegel, biochemist and leader of the Molecular Parasitology research group at the Biomedical Center., which is transmitted via tsetse flies and causes African sleeping sickness in humans and nagana pest in animals."Trypanosomes are masters at hiding from the immune system through antigenic variation," says Siegel."Their cells are enshrouded by a dense, homogeneous coat of surface glycoproteins, which they switch in periodic, non-random patterns." Until now, little was known about the mechanisms behind these changes in antigen expression. This gap in our knowledge has been filled by the study led by Colomé-Tatché and Siegel, which has discovered how the sequence of antigen expression is determined."We can now predict which antigen is activated next and appears on the surface of trypanosomes," says Colomé-Tatché. In addition to experts from LMU, the study included researchers from Helmholtz Munich and international cooperation partners from the United States and the United Kingdom. One of the biggest challenges for the team was to track transcriptome changes and potential genomic rearrangements in individual cells during a switch event. For that, the researchers established a highly sensitive single-cell RNA sequencing approach to accomplish precisely this task. An important trigger for antigen switching is a double-strand break in the transcribed antigen-coding gene."Our data show that the type of repair mechanism and the resultant antigen expression depend on the availability of a homologous repair template in the genome," says Colomé-Tatché. When such a template was available, repair proceeded through segmental gene conversion, creating new, mosaic antigen-coding genes. Conversely, in the absence of a suitable template, a telomere-adjacent antigen-coding gene from a different part of the genome was activated. The research team is convinced that the discovery of these mechanisms for controlling antigenic variation can make a decisive contribution to the development of new drugs -- and not just against trypanosomes, but also many other pathogens."Additionally, our study demonstrates the power of highly sensitive single-cell RNA sequencing methods in detecting genomic rearrangements that drive transcriptional changes at the single-cell level," says Siegel.Zhibek Keneskhanova, Kirsty R. McWilliam, Raúl O. Cosentino, Anna Barcons-Simon, Atai Dobrynin, Jaclyn E. Smith, Ines Subota, Monica R. Mugnier, Maria Colomé-Tatché, T. Nicolai Siegel.Our immune system is always on alert, detecting and eliminating pathogens and cancer cells. Cellular control mechanisms cause diseased cells to present antigens on their surface like signs for the ... A new study shows how key features on the surface of HIV-infected cells help the disease evade detection by the immune system. It also shows how these features can be ... Scientists have discovered a new way to control the immune system's 'natural killer' cells, a finding with implications for novel cell therapies and tissue implants that can evade immune ... Scientists are increasingly trying to use the body's own immune system to fight cancer. A new study now shows the strategies tumor cells use to evade this attack. The method developed for this work ...
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