Plague pathogens bypass the immune system

Yersinia has spread fear and terror in the past, and the plague pathogens are still not eradicated. The bacteria inject various enzymes, into the macrophages of the immune system. There, it is activated and prevents the defense cells from enclosing and digesting the plague bacteria.

"Yersinia trick the macrophages of the immune system"

Yersinia has spread fear and terror, especially in the past, but the plague pathogens are still not completely eradicated today. The bacteria inject various enzymes, including the enzyme YopO, into the macrophages of the immune system. There, it is activated and prevents the defense cells from enclosing and digesting the plague bacteria.

Yersinia also includes the plague pathogen, which caused fear and terror worldwide until the discovery of antibiotics. The major 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 found in wild rodents. The transmission occurs mainly via fleas, but also via droplet infection. "Yersinia tricks the macrophages of the immune system," said Dr. Gregor Hagelüken of the Institute of Physical and Theoretical Chemistry at the University of Bonn.

The structural biologist investigated the peculiarity of the plague pathogens, a kind of syringe with which they inject the enzyme YopO and some other enzymes into the macrophages of the immune system. However, YopO only becomes active when it binds to the actin of the scavenger cell. Normally, the structural protein actin helps the phagocyte to form protrusions with which it flows around the pathogens and then crushes them. During this process, the phagocyte calls for help from other defense cells.

YopO disrupts the immune system’s communication

"As soon as YopO has bound to the actin, however, it helps to disrupt communication within the macrophage, which then no longer attacks," reported Hagelüken. "The Yersinia remain ultimately undisturbed." Researchers have been wondering for some time how YopO is activated by the binding to actin and thus how the switch for the dramatic progression is flipped. "Scientists at Oxford University and the National University of Singapore deciphered the structure of the actin-bound YopO as early as 2015," reported lead author Martin F. Peter. However, the structure shots were a kind of "still image": it was not recognizable how the YopO changes its shape when it binds to the actin.

"Enzymes are not stiff structures, but have several mobile `hinges ́ with which they can change their form," Hagelüken continued. The researchers wanted to take two "snapshots": One of YopO alone and one of the YopO/actin complex. These "before and after pictures" should show how the two partners change their shape as a result of the complex formation. "This idea was a challenge because the normal method of crystal structure analysis did not work with the free YopO. As it turns out, it is too flexible to form ordered crystals," said Peter.

Latest tools for structure elucidation

The scientists of the University of Bonn, therefore, used several instruments from the toolbox of structure elucidation. Extremely intense and focused X-rays can be used to study the overall structure and structural changes of enzymes dissolved in water with the aid of small-angle X-ray scattering.

In addition, the researchers attached spin markers to certain positions of the YopO and actin. They function like survey points in the landscape at which, for example, the exact location of a property can be determined. "Using the spin markers, we can use a molecular ruler - the PELDOR method - (PELDOR stands for Pulse Electron-Electron Double Resonance) to measure the nanometre distances between these positions and determine how YopO and actin change shape," reported Hagelüken. So far it has been assumed that YopO performs a folding movement like scissors as soon as it binds to actin. The new results indicate, however, that this is not a larger movement, but many small ones, with which YopO enters the active state.

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