How Pesterreger tricks the immune system
Yersinia, especially in the past, has sown fear and terror, but even today, pests are not completely eradicated. The bacteria inject various enzymes, including the enzyme YopO, into the phagocytes of the immune system. It activates and prevents immune cells from surrounding and digesting the plague bacteria. Using the latest methods, scientists at the Institute of Physical and Theoretical Chemistry at the University of Bonn have now understood how YopO changes its shape and thus helps to disrupt the immune system. The results are now published in the journal "Structure".
Yersinia also includes the pest that has caused anxiety and horror around the world until the discovery of antibiotics. The main epidemics are over, but the World Health Organization (WHO) reported a total of 1,451 deaths in 21 countries between 1978 and 1992. Plague bacteria are also present in wild rodents. Transmission is mainly by fleas, but also by droplet infection. "Yersinia deceives the macrophages of the immune system," says Dr. Gregor Hagelüken of the Institute of Physical and Theoretical Chemistry at the University of Bonn.
The structural biologist has already done research on Yersinian as a PhD student at the Helmholtz Center for Infection Research in Braunschweig. The harmful irritant is a type of syringe that injects the enzyme YopO and other enzymes into the phagocytes (macrophages) of the immune system. YopO becomes active only when it binds to the actin of the phagocyte. Normally, the actin structural protein helps phagocytes to form protuberances around which it infuses pathogens and then dissociates them. En route, the Fresszelle calls new defense cells.
YopO confuses the communication of the immune system
"But as soon as YopO binds to actin, it helps to disrupt communication within the macrophage – it can no longer attack," reports Hagelüken. "The Yersinia are finally not worried." Researchers have long wondered how YopO is activated by binding to actin and the switch of the dramatic process is therefore denied. "Scientists from the University of Oxford and the National University of Singapore have already decoded the structure of the YinO-related YopO in 2015," reports Martin F. Peter, Hagelükens' collaborator and lead author . However, the structural images were a kind of "still image": it was not clear how the YopO changed shape when it bound to actin.
"Enzymes are not rigid structures, but have a number of" hinges "that allow them to change shape," explains Hagelüken. The researchers wanted to take two "snapshots": one from YopO alone and the other from the YopO / actin complex during a second round. These "before-after images" were meant to show how both partners are changing shape through complex training. "This idea was difficult because the normal method of crystalline structure analysis did not work for free YopO, and in the end it is too soft to form ordered crystals," says Peter.
Latest structural recognition tools
Scientists at the University of Bonn have therefore used several instruments of the toolbox for the elucidation of structures. With Dr. Dmitri Svergun from the European Molecular Biology Laboratory in Hamburg used the PETRA III electron accelerator of the German electron synchrotron DESY. "By using extremely intense and concentrated X-rays, what is known as small-angle X-ray diffraction can be used to study the overall structure and structural modifications of dissolved enzymes in water," explains Svergun.
In addition, the researchers applied spin markers at certain positions of YopO and actin. They function as surveying points in the landscape, where, for example, the exact location of a property can be determined. "Using spin markers, we can use a molecular linear method – the PELDOR method – to measure the nanometric distances between these positions and thus determine how YopO and actin change shape," says Hagelüken. Until now, it has been suggested that YopO behaves like a pair of scissors when it binds to actin. "However, our results suggest that it's not a big move, but a lot of small ones, with the YopO in the active state," Peter said.
Foundations for custom substances
Detected in time, the plague can be cured with antibiotics. "However, bacteria can become resistant to the frequent use of antibiotics, which means that the drugs no longer work properly," said Hagelüken. If the basic processes of pathogens beyond the immune system are better understood, more personalized substances can be developed to inhibit them.
Dr. Gregor Hagelüken
Institute of Physics and
University of Bonn
Martin F. Peter, Anne T. Tuukkanen, Caspar A. Heubach, Alexander Selsam, Fraser G. Duthie, Dmitry I. Svergun, Olav Schiemann and Gregor Hagelueken: Study of Conformational Changes in Yersinia Type III Effector YopO Secretion in Biological Solution Structural Integration, Journal "Structure", DOI: 10.1016 / j.str.2019.06.007
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