Researchers from the Hebrew University of Jerusalem and the University of North Carolina at Charlotte have discovered that the CARDIB protein normally suppresses the sea anemone's antiviral response, but in its absence, viruses multiply more easily. The finding suggests that animals have evolved different solutions to deal with viral infections.
A protein that suppresses immune system It sounds like a weakness: if it inhibits the response against viruses, one would expect its removal to strengthen the defense. But an experiment inSea lilies yielded the opposite result. After the researchers disabled the gene responsible for the protein, the animals became more vulnerable to infections and carried a greater amount of viruses.
The protein, named CARDIB, is at the center of new research led by doctoral student Sharoni tone And Prof. Yeho Moran from the Department of Ecology, Evolution and Behavior at the Hebrew University, in collaboration with researchers from the University of North Carolina at Charlotte. The study was published in the journal Nature Ecology & Evolution.
The findings point to an antiviral pathway that is different from the mechanism known in humans and other vertebrates. They also demonstrate that similarity in the structure of proteins does not guarantee that they will fulfill the same biological function.
A protein that looks familiar – but behaves in the opposite way
In humans and vertebrates, one of the key proteins in the response to viruses is MAVS. When sensors within the cell recognize viral genetic material, MAVS helps trigger a signaling cascade that leads to the production of antiviral substances and activation of the innate immune system.
The researchers wanted to test how ancient this mechanism is, and turned to sea anemones. Sea anemones belong to the order Cnidaria, along with corals and jellyfish. Their evolutionary branch separated from the branch that led to humans more than 600 million years ago, so they may provide a glimpse into the immune systems of ancient animals.
During the study, a previously unknown protein was identified, CARDIB – short for CARD Inhibitor Binding Protein. Its structure reminded the researchers of components found in the MAVS pathway, so the initial hypothesis was that it also exerts antiviral defense.
“Everything we knew about CARDIB suggested that it should act like MAVS,” said Prof. Moran. “Instead, we found that it does exactly the opposite. Instead of activating the antiviral defense, CARDIB usually suppresses it.”
Gene editing born from an anti-viral immune system
To examine the role of CARDIB, the researchers used CRISPR to knock out the gene that produces the protein in sea anemones. This is a kind of scientific closure: the technology used today for gene editing evolved from research into the ongoing war between viruses and the immune systems of living creatures.
The CRISPR-Cas system was originally discovered as a defense mechanism for bacteria and archaea against viruses that attack them, called bacteriophages. The system retains segments of the genetic material of previous viruses and uses them to recognize and cut viral genetic material upon reinfection. In an interview with the Haydan website, Prof. Virginios Shikschinis said that his team He studied how a bacterium used to produce yogurt defends itself against viruses, without planning to develop a gene editing tool..
The fight is not one-sided. Viruses are also evolving and creating ways to bypass bacterial defenses. Weizmann Institute research, which we reported on in the article "When viruses win", showed how viruses can outsmart the immune system of bacteria. It is this arms race between bacteria and viruses that has given science one of the most important research tools of recent decades.
Once researchers understood how the CRISPR system recognizes and cuts a specific genetic sequence, they adapted it to edit DNA in the lab. Among the scientists who pioneered its transformation into a technology were Emmanuel Charpentier, Jennifer Doudna, and Virginios Shikschinis, who were also recognized for their contributions to the development of CRISPR-Cas9, including The Technion Harvey Award.
Since then, a broad infrastructure has developed around the technology, designed to improve editorial planning and adapt it to research, medicine, and agriculture. In Israel, a CRISPR-IL consortium, which combines computational tools and artificial intelligence in gene editing designAt the same time, an effort is being made to measure the accuracy of editing and identify unwanted changes; Israeli researchers have developed, for example, A method for quantifying errors caused during genome editing using CRISPR.
In the current study, the technology was used to test an entirely different type of antiviral immune system. The researchers disabled CARDIB, expecting that removing a suppressor protein would release the brakes and allow for a stronger response. In fact, the opposite occurred: in sea anemones without CARDIB, viruses multiplied more easily, defense pathways were not activated properly, and the animals’ ability to cope with infection was impaired.
From the aquarium to a more natural marine environment
One of the strengths of the study was that the researchers didn’t limit themselves to laboratory conditions. The genetically modified sea anemones were transferred to outdoor marine experimental systems in South Carolina. These systems, called mesocosms, received natural water from a river mouth and contained a variety of viruses and microorganisms from the environment.
Within a few days, sea anemones lacking CARDIB and other genes in the antiviral pathway accumulated more viruses than animals that had not undergone genetic modification.
The move from the aquarium to a more complex system was important because in the laboratory, animals are usually exposed to a limited number of conditions or pathogens. In nature, many viruses, bacteria, temperature changes, and interactions with other creatures are simultaneously at work.
One gene that appeared to be of moderate importance in laboratory experiments turned out to have a much more significant role under complex environmental conditions. This result highlights that the function of the immune system is not always fully understood under controlled conditions.
More than one way to fight viruses
The similarity between CARDIB and components found in the human pathway might have led to the conclusion that the defense system has remained virtually unchanged for hundreds of millions of years. The study suggests a more complex picture.
The same structural components, or similar ones, can be integrated into different immune networks and play opposite roles. In vertebrates, a protein like MAVS serves as a focal point for activating the response. In the sea anemone, CARDIB acts as a suppressor, but also as an essential part of the system that allows the animal to defend itself.
This suggests that evolution did not necessarily invent a single antiviral pathway and then conserve it across all animals. Different groups may have used similar molecular building blocks to assemble different defense mechanisms.
The finding is also relevant to the study of corals, relatives of sea anemones. Viruses can affect coral health and their response to environmental stresses, but the current study did not examine corals directly. So it is too early to conclude how CARDIB or similar pathways affect coral reefs.
This should not be used to infer treatment of humans.
Despite the comparison to human MAVS, the study addresses the evolution and basic function of the immune system in sea anemones. It does not offer a new treatment for viral infections in humans, and it is not assumed that blocking human proteins or suppressing the immune response will work in a similar way.
Its main importance is in expanding our understanding of the diversity of immune systems in the animal world. Sea anemones seem simple compared to vertebrates, but they have been dealing with viruses for hundreds of millions of years. The mechanisms they have evolved may reveal new principles of immune control and challenge the assumption that the human immune system represents the only possible model.
More on the subject on the science website
- Research about How a bacterium used to produce yogurt defends against viruses led to the discovery of CRISPR without the researchers having planned to develop a gene editing tool in advance
- When viruses win: How viruses stack up against the immune system of bacteria
- Harvey Prize for the developers of the CRISPR-Cas9 gene editing technology
- CRISPR-IL combiner combines artificial intelligence to advance gene editing
- A method for quantifying errors caused during genome editing using CRISPR
