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The Tail of a Bacterial Martyrdom

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The tree of life connects all living organisms on earth, including animals, plants, bacteria, and fungi. Even though all those organisms are vastly divergent, they have at least one thing in common: They are all infected by microorganisms. And consequently, they have developed strategies to fight their invaders.

Until now, it was assumed that the defense strategies of a bacterium would not share any major similarities with the human ones. Yet, this notion was challenged in recent years by discoveries of conserved defense strategy components (also called immune modules which can refer to complete proteins or only fractions of proteins) against microbial invaders across the tree of life. Only in July this year, researchers coined a name for this novel concept: ancestral immunity.

A shared defense strategy of bacteria and humans

Phages, or more precisely, bacteriophages are viruses that amplify within infected bacteria. Eventually, the bacteria burst open and release the newly produced phages. In order to protect themselves, bacteria have developed quite an impressive arsenal of immune strategies against their invaders. Researchers at the Weizman Institute of Science in Rehovot in Israel recently described an antiphage defense system in bacteria which is very similar to an immune module in humans. In human immunity, a small human protein called ISG15 is attached to both viral and human proteins. This helps the human cell eliminate viral infections through a mechanism which has not been fully resolved. The attachment process requires a specific set of proteins called E1, E2, E3, and DUB.

The researchers from the Weizman Institute found four proteins in bacteria which share high similarity with exactly those human proteins: a small protein like ISG15 (termed Ubl), and three proteins that look like E1, E2, and DUB. This set of proteins was termed the Bil system and could protect bacteria against many different bacteriophages. By changing the bacterial protein sequences based on prior knowledge obtained from the human system, the researchers showed that the bacterial proteins likely fulfill similar functions as their human counterparts.

Altered tail structure “sterilizes” bacteriophages

The more phages you add in the beginning, the more bacteria will be immediately infected simply due to reasons of quantity. As phage infection kills the bacteria, more bacteria will die right away. In contrast, infection with a small number of phages only reaches a limited number of bacteria in the beginning. They die and release newly produced phages that will infect the rest of the culture. After a while, the remaining bacteria will also die. The researchers discovered that bacteria that possess the Bil system could survive infection with a small but not a high number of phages. Consequently, the researchers came up with the idea that the newly produced phages might be non-infectious to the remaining bacteria.

They isolated bacteriophages from bacteria cultures with the Bil system and characterized them using electron microscopy. With this method, one can visualize tiny structures in the nanometer range which are not visible under a normal microscope. Two different phage types were observed: the first one looked normal, with an icosahedral head and a tail, but the second type was missing the tail structure. Because the tail is important for the initial contact with the bacteria and for injecting their reproductive information, this type of phage was clearly not infectious.

But why would the first type, a fully intact phage with a tail be non-infectious? To make a long story short, the researchers discovered that the Bil system attaches the Ubl protein very specifically to the phage protein CTF which forms the tip of the phage tail. This attachment can either result in tailless phages (the second type) or in non-infectious, tailed phages (the first type) because the attached protein blocks the contact with the bacteria.

Bacteriophages are composed of an icosahedral head, a tail, and the CTF protein, which forms the tip of the tail. In infected bacteria that possess the Bil system, Ubl is attached to the CTF protein. As a result, tailless phages or phages with a Ubl-modified tail are produced which are both non-infectious. Image source: Created by the author with BioRender.com

A bacterial sacrifice for the greater good

In contrast to other defense strategies, the Bil system does not prevent the phage-infected bacteria from dying. Instead, the Bil system manipulates the phages to become non-infectious to the remaining bacteria. It protects the bacteria at the population level from spreading phage epidemics due to the brave, or rather unlucky bacteria that sacrifice themselves to protect their peers.

The Bil system is only one of many recently discovered immune modules shared by different species across the tree of life. These discoveries might be the start of a paradigm shift in how researchers conceive and study defense strategies against microbial invaders in distantly related species. And it opens up new avenues for gaining knowledge from bacteria about the human immune system, and vice versa.

Link to the original post: Hör, J., Wolf, S.G. & Sorek, R. Bacteria conjugate ubiquitin-like proteins to interfere with phage assembly. Nature 631, 850–856 (2024). https://doi.org/10.1038/s41586-024-07616-5

Featured image: created by author using Bing Image Creator