Phage Tail Modification by Bacteria: New Insights into Human Immune System from Israeli Scientists

(l-r) Dr. Jens Hör and Prof. Rotem Sorek (Weizmann Institute of Science)

Weizmann Institute of Science researchers revealed a bacterial immune system that thwarts the phages’ plot by attaching a small protein molecule to their tails. The components of this new immune system are similar in structure to a human immunity mechanism, and they might help reveal how this mechanism works and how our own immune system has evolved.

In the new study, published in Nature, researchers led by Dr. Jens Hör from Sorek’s laboratory discovered a new bacterial immune system that contains a ubiquitin-like protein with a structure similar to that of ISG15, one of the more mysterious proteins in the human immune system. ISG15 plays a role in the defense against different viruses, such as influenza and HIV, but how it performs its task is not entirely clear.

Phages, viruses that attack bacteria, have a head and a tail. The head contains the phage’s genetic material and the tail is used to identify a potential host, that is, a bacterial cell into which it can inject this material. Once the injection is complete, the phage hijacks the bacterium’s cellular machinery and forces it to produce new copies of itself, which ultimately burst the cell and infect other bacteria in the colony.

The first antiphage defense mechanisms in bacteria were discovered in the 1960s, but only a handful of such mechanisms were known until recently. The most famous of these is CRISPR-Cas9, whose discovery led to a revolution in gene editing. In recent years, however, there has been a wave of new findings in the field, leading to the discovery of more than 150 new bacterial immune systems with varied modes of action. Many of these systems were identified using a method developed by Prof. Rotem Sorek of Weizmann’s Molecular Genetics Department.

Sorek’s method is based on a strikingly simple principle: Genes involved in bacterial immune mechanisms tend to cluster together in the bacterial genome, in areas known as “defense islands.” Researchers can therefore discover new immune systems by examining genes with unknown function that are located close to known defense islands. “In many of our studies, we have recognized components of bacterial immune systems that were familiar to us from extensively studied human immune mechanisms,” Sorek explains. “This suggests that the evolutionary source of a large part of our innate immune system comes from bacteria. Our new study provides further support for this idea.”

Ubiquitin is a small, highly conserved protein found in all eukaryotic cells. It plays a critical role in many cellular processes by acting as a tag that can be attached to other proteins. This process, called ubiquitination, can target proteins for degradation, regulate their activity, or affect their location within the cell.

Ubiquitin itself is a protein consisting of 76 amino acids. It has a simple structure, but it can be attached to other proteins in a variety of ways. The most common type of ubiquitination is monoubiquitination, in which a single ubiquitin molecule is attached to a protein. However, ubiquitin can also form chains, in which multiple ubiquitin molecules are linked together. The specific way that ubiquitin is attached to a protein can determine its fate. For example, a protein with a chain of ubiquitin attached to a specific lysine residue is typically targeted for degradation by a cellular machine called the proteasome.

In the 1970s, scientists uncovered a cellular control system capable of altering the structure and role of proteins, as well as their lifespan, by attaching a small protein called ubiquitin to them. Since ubiquitin’s discovery – for which professors Aaron Ciechanover, Avram Hershko and Irwin Rose were awarded the 2004 Nobel Prize in Chemistry – other scientists have revealed many similar systems, in which enzymes attach various small proteins to the target protein, thereby changing its destiny.

Hör and his team discovered a unique bacterial immune system unlike any seen before. This system didn’t stop viruses from entering the cell and replicating. Bacteria with this system still died after infection, producing new viruses. However, these new viruses were rendered infertile, unable to infect other bacteria. This suggests the immune system disrupts the virus’s ability to spread within the bacterial colony, even though it can’t prevent initial infection.

To understand how the duplicated viruses lose their ability to infect other cells and what role the new bacterial immune system plays in this, Sorek’s research team joined forces with Dr. Sharon Wolf, head of the Electron Microscopy Unit in Weizmann’s Chemical Research Support Department. The researchers labeled the ubiquitin-like protein at the heart of the new immune system with gold particles that are clearly visible under the microscope.

When they looked at the images of duplicated phages, they were astonished. The labeled protein located itself at the end of the viral tail, preventing the phages from using their tails to locate and infect new bacterial cells. The researchers believe that this new immune system is capable of recognizing the three-dimensional structure of the viral tail, which allows the system to work effectively against a wide variety of phages, as long as they have tails with a similar structure.

“We hope that our discovery in bacteria will inspire researchers studying the human immune system to examine whether a similar principle applies to the human immune protein ISG15. Viruses that attack humans may not have tails, but it is possible that human defenses also work by disrupting a key structural protein of the virus,” Sorek says. “The immune system that we explored in this study is just one of many systems containing ubiquitin-like proteins that we identified in the bacterial genome. Now, it remains to be seen how those other systems fight their old enemies, the viruses.”