Particularly in the fight against antibiotic resistance, the new findings from the University of Copenhagen could lead to enhanced efficacy of treatments with viruses to fight infection, researchers explain.
Imagine a city under constant threat from invaders. The city's defense system deploys a sophisticated anti-missile defense mechanism to neutralize threats before they can cause harm.
In the microscopic world, bacteria face a similar scenario. For every bacterium out there - good and bad - there are around 10 viruses, also called 'bacteriophages' or simply 'phages'. Each of these viruses are tailored to infiltrate bacteria, causing infection in our benign bacteria and can contribute to antibiotic resistance for the malign bacteria.
Now, a recent study from the University of Copenhagen reveals how bacteria use a defense mechanism called Zorya to protect themselves from viral attacks. The system detects and degrades viral DNA before the virus can replicate, much like a city's defense system intercepts incoming missiles.
"A lot of anti-phage defense systems cause cell death, meaning that the cell self-exterminates and sacrifices itself to prevent the virus from spreading to its sister cells. Surprisingly, we discovered that Zorya treats the infection while leaving the cell intact - obviously this is very powerful for the cell as it ensures its survival," explains Associate Professor and Group Leader at the Novo Nordisk Foundation Center for Protein Research Nicholas Taylor, corresponding author of the study.
The study was conducted with great help from researchers at Humboldt-Universität zu Berlin in Germany, University of Otago in New Zealand, ETH Zürich in Switzerland and Oxford University in Great Britain.
Promise for new treatments
The study shows how bacteria adapt their molecular machinery to fend off threats, with potential implications for medicine and biotechnology.
"Revealing the mechanism of the Zorya anti-phage defense system and demonstrating its ability to detect and combat phages at the early stages of infection represent significant advancements in understanding this novel defense mechanism," says Nicholas Taylor.
The discovery not only deepens our understanding of bacterial defense but also holds promise for new treatments against antibiotic-resistant infections and the development of artificial antiviral systems, says Nicholas Taylor.
The findings could also lead to future applications, for instance designing medication/inhibitors that can block the defense system in malign bacteria, thus improving clinical phage therapy. Something that is particularly interesting in the fight against antibiotic resistance.
"Additionally, our results may inspire the development of artificial anti-viral defense systems, which could detect viral infections," says first author Haidai Hu.
A myriad of advanced technologies
To understand how the Zorya defense system works, the researchers used several advanced techniques, including cryo-electron microscopy which help see very small structures, mutagenesis, meaning changing genes to study their function, and fluorescence microscopy which is using glowing markers to see inside cells. They also utilized proteomics, which basically is studying proteins at a large scale, and other functional studies.
"We took the genes that make up the Zorya system - ZorAB, ZorC, and ZorD - and inserted them into bacteria that didn't have this defense system. When these modified bacteria were exposed to various viruses, they showed strong protection against infection. This means the Zorya system can directly fight off viruses without killing the bacterial cell," says Nicholas Taylor.
"Using cryo-electron microscopy, we looked at the structure of the ZorAB complex in great detail. We found that it works like a tiny motor powered by protons. This motor helps the bacteria detect a virus attack and sends signals to activate other parts of the Zorya system. These parts then break down the viral DNA, stopping the virus from spreading".
The study represents a significant advancement in our understanding of bacterial defense mechanisms. Future research will likely focus on further elucidating the molecular details of the Zorya system and exploring its potential applications in medicine and biotechnology.
Read the full study "Structure and mechanism of the Zorya anti-phage defense system".
