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We often refer to bacteria as the causes of disease, but bacteria can also "get sick" with viruses called phages

A system responsible for editing and controlling the genes. Illustration: shutterstock
A system responsible for editing and controlling the genes. Illustration: shutterstock

We often refer to bacteria as the cause of disease, but bacteria can also "get sick". Viruses, called phages, attack bacteria and multiply inside them. The bacteria, for their part, fight these viruses using a unique immune system. Like the immune system in our body, the system developed by the bacteria is also based on the ability to recognize foreign factors, and to distinguish between them and components of the bacteria itself. This distinction is the main challenge any immune system faces. Scientists from the Weizmann Institute of Science and Tel Aviv University have revealed the mechanism by which the immune system of bacteria differentiates between the DNA of the viruses that infect them and their own DNA. These findings were published recently in the scientific journal Nature.

Right: Prof. Rotem Sorek and Dr. Gil Amitai next to the sculpture "Aiming for the Stars", made by sculptor Phyllis Cushland
Right: Prof. Rotem Sorek and Dr. Gil Amitai next to the sculpture "Aiming for the Stars", made by sculptor Phyllis Koshland

"Phages are just as common as bacteria, and often they are even more common," he saysProf. Rotem Sorek From the Department of Molecular Genetics at the Weizmann Institute of Science. "And like all viruses, phages also use the molecular mechanisms of the host cell to replicate themselves - at the expense of the host. Therefore, if the bacteria are living things, they must develop and activate an effective immune system."

The understanding that bacteria have a "learning" immune system - one that produces immune memory - is relatively new, and it only took shape when a learning bacterial immune system called CRISPR was discovered a few years ago. This is a complex system that allows the bacterium to "remember" previous viral attacks, and effectively defend itself against repeated attacks by those viruses. During the first infection, the system "steals" a short segment from the DNA of the virus, and stores it in a special place in the genome of the bacterium. This segment makes up the immune memory, and the CRISPR system uses it to detect repeated infections of the same virus. The system produces a short strand of RNA from the segment, and a match between this strand and the genetic sequence of the next virus that invades the bacterium directs the system to destroy the viral DNA.

Misidentification of one's own genetic material - as if it belongs to a foreign invader, may cause the bacterium to attack and destroy essential parts of itself (a kind of autoimmune disease). The consequences of such a mistake can be fatal for the bacteria. "When there is approximately 100 times more self-DNA than foreign DNA in a cell," says Prof. Sorek, "there is room for many such fatal mistakes."

Dr. Assaf Levy

How does the CRISPR system know how to "steal" only parts of foreign DNA, and not parts of the bacterium's own genome? Prof. Shurk and research student Dr. Asaf Levy (who is currently doing his post-doctoral research in the United States) - in collaboration with Prof. Ehud (Odi) Kimron and research student Moran Goren from Tel Aviv University - tackled this question, and revealed a complex and numerous mechanism of action - Shelby The experiment they performed focused on plasmids - short, circular pieces of DNA that mimic viruses - which they inserted into bacterial cells. The scientists discovered that the CRISPR system recognizes the DNA of the plasmid, and creates new immune segments from it with high efficiency, while the DNA of the bacteria is almost not attacked by the system. In the study, 38 million different vaccination events were examined. In a careful examination of the segments taken from the plasmid, the scientists discovered that the system knows how to identify DNA that replicates at a high rate. Thus, ironically, the survival tactic of the virus - replication at any cost - is what helps the bacterium fight it. The scientists realized that small fragments in DNA, which are created during replication, are the source of the segment that the CRISPR system "steals" and turns into an immune segment. When the DNA is broken, an enzyme is activated which repairs it. This enzyme cooperates with the CRISPR system - and leads to the collection of the foreign DNA.

"The identification of the fragments in the DNA copies as a source of new immune segments was a breakthrough," says Prof. Sorek, "but he has not yet given a full explanation for this phenomenon. Breaks also occur spontaneously in the DNA of the bacteria, and we still do not understand how the CRISPR system avoids attacking the DNA of the bacteria in such cases."

The solution was found when the DNA repair process was understood in its depth: when a DNA break occurs, the repair enzyme "gnaws away" a little of the broken DNA before it repairs the break. When the enzyme encounters a certain sequence of eight bases, called the chi site, the milling process stops, and the broken sequence is repaired. The chi sequences are found in very high density throughout the bacterium's genome, so the repair enzyme gnaws away at only a small amount of bacterial DNA during break repair. But in viruses, as well as in plasmids, chi sequences are very rare, and thus the repair enzyme, and with it the CRISPR system, gnaw large parts of the viral genetic sequence following a break, and the gnawing products are the source of the immune segment used by the CRISPR system. Thus, the chi sequences allow the bacterium to recognize its own DNA, and prevent the CRISPR system from attacking the bacterium itself.

"The question of how the bacteria's immune system prevents itself from attacking the bacteria itself was a central puzzle in the field, and we solved it," says Prof. Sorek. "Solving the riddle not only allows us to understand the day-to-day war between bacteria and viruses in depth, but also opens a window for more intelligent uses of the system as a biotechnological tool in the food industry."

A new immune system

The CRISPR system is a highly effective immune system, but it is only found in 40% of bacteria. If so, how do the other bacteria - lacking CRISPR - deal with viral attacks? In the laboratory of Prof. Rotem Sorek, they recently discovered a completely new immune system, called BREX. This system is found in 10% of all bacteria, and protects them from a wide range of viruses. The study, carried out by research student Hila Zebro and post-doctoral researcher Tamara Goldfarb, Released In the scientific journal EMBO Journal.

 

2 תגובות

  1. Phages have been used in Russia with Greek success instead of antibiotics since at least the 70s, so there is no discovery here.
    But now that all the existing antibiotics are losing their effectiveness, and the development of antibiotics takes decades, there is reason to think about a phage that, unlike antibiotics, evolves at the same time as the bacteria it fights.

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