Can a bacterium get rheumatoid arthritis? Not quite, but new research at the Weizmann Institute of Science shows that bacteria can suffer from a type of autoimmune disease – one in which their immune system mistakenly attacks their own cells, just as it does in human autoimmune diseases. In the case of the bacterium, such disease can kill it or leave its immune system crippled.
In autoimmune disease, the immune system that clears the body of harmful invaders seems to get confused, identifying the body’s own proteins as foreign and attacking them. Nonetheless, the immune system is a necessity, even in bacteria: Viruses that infect and kill bacteria are abundant; without an immune system, bacteria would have become extinct. In the past, scientists had assumed that bacteria had only the crudest of immune systems to aid them in fighting viral infection – one that is set in the genes and passed on unchanged to further generations. Only recently was it discovered that many bacteria have a second, more sophisticated kind of immune system, known as an adaptive immune system because it can learn to fight a virus it has never encountered before.
“In fact,” says
Dr. Rotem Sorek of the Institute’s Molecular Genetics Department, “the bacterial immune system seems to have an advantage over the human version of adaptive immunity, because it not only stores information on previous bouts of infection, as in humans, but also passes the immunity on to daughter cells in its genes. As opposed to human infants, whose adaptive immune system is more or less a blank slate at birth, new bacteria benefit from the experience of the parents’ illnesses.”
The bacterial adaptive immune system is much simpler than of its counterpart in humans, but the principle is similar: Identify certain molecular patterns of the invader and then generate antibodies that attack anything with a matching pattern. The bacteria accomplish this using a genetic system known by the acronym CRISPR. During the first encounter with an invading virus, CRISPR captures snippets of viral DNA and holds them in so-called “immunity cassettes” in the bacterial genome. In subsequent infections, the CRISPR system uses these cassettes to produce small RNA molecules that act as antibodies, binding to the viral genetic material and blocking the viruses from replicating. These DNA samples are kept “on file,” and new immunity cassettes are added in anticipation of future threats.
To understand the bacterial immune system, Dr. Adi Stern, a postdoctoral fellow in Sorek’s group, together with Sorek,
analyzed existing data on thousands of CRISPR immune cassettes. What they saw took them by surprise: Every once in a while a bit of the bacterium’s own DNA, rather than that of a virus, showed up as an immunity cassette. After further analysis, they realized that capturing self-DNA in the immune cassette that was supposed to hold viral DNA was a mistake that had drastic consequences for the bacterium: Its own DNA came under autoimmune attack. “To survive,” says Sorek, “the bacteria ended up shutting down their adaptive immune systems. Their only other option was to die. We really didn’t expect to find this kind of disease – one we think of as affecting only higher animals – in bacteria.”
Sorek: “Clearly, there’s a cost to having a sophisticated immune system. Only about half of all bacteria have adaptive immune systems; we think the risk of autoimmune disease might be too high for some. This twist gives us a new perspective on the tangled evolution of infection and immunity: Viruses evolve rapidly to evade the adaptive immune system, which races to keep up. In this fierce competition, it becomes harder and harder to distinguish between ‘self’ and ‘other,’ and mistakes may be the natural consequence.”
“Our goal now,” adds Sorek, "is to understand how we might induce this autoimmunity in bacteria. If we manage to inflict autoimmunity on disease-causing bacteria, we will make them more vulnerable and help our bodies to clear them more easily. Ironically, we plan to use the defense mechanism of bacteria as a weapon against them. This opens an exciting window on the development of new antibiotics.”
Dr. Rotem Sorek’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; and the Leona M. and Harry B. Helmsley Charitable Trust. Dr. Sorek is the incumbent of the Rowland and Sylvia Schaefer Career Development Chair in Perpetuity.
Helpful Bacteria, Harmful Viruses
Outside the human intestine, bacteria are known to be attacked by viruses called phages, and these can sometimes kill large numbers of bacteria in a short time. The question is: Are the gut bacteria also susceptible to phage infection? And, if so, what viruses are involved and which bacteria do they attack? These questions have not received much attention until now; they were the focus of recent research by Dr. Rotem Sorek of the Molecular Genetics Department. The findings recently appeared in Genome Research.
To investigate the viral population of the gut, the researchers had use of a surprising “catalog”: pieces of viral DNA that are stored in the immune systems of bacteria. The apparatus, called CRISPR, defends bacteria against viruses. When a virus gets inside a bacterial cell, CRISPR steals a small bit of the virus’s DNA and stores it in the part of its own genome that is designed specifically for this immune function. The next time the same virus infects the cell, its immune system will use the stored viral DNA to identify and destroy the invader, something like the way that antibodies work in the human body. For the scientists, these sequences lined up in the bacterial immune systems could be read as a sort of historical record of the viruses that have attacked the various gut bacteria.
Besides giving researchers the largest collection of information to date on phages in the human gut, the team’s findings have yielded new insights on the relationships between gut bacteria, the viruses that infect them and the humans who host them. For example, the scientists discovered that large groups of people share the same viruses, and about 80% of the viruses the team identified were found in more than one person. A comparison with samples from Americans and Japanese showed that they, too, shared the same strains. Considering the wide variety of viruses generally found in nature, this is a surprising finding; the scientists believe it may be tied to fact that the gut is a closed environment.
Another finding was that viruses are sometimes inserted into the bacterial DNA in their entirety. Sorek: “Phages occasionally contribute to the bacteria genes for antibiotic resistance. In return, the bacteria host the phages’ DNA and pass it from person to person. It’s a tradeoff that has evolved to benefit both sides.”
A comprehensive database of phages and the gut bacteria they infect may have implications for research on human health. For instance, if a certain bacterium is known to provide protection against allergies, one could check the effects of the virus that attacks that bacterium. “The ultimate goal,” says Sorek, “would be to create a vaccine against that virus, which would help the bacterium. In other words, aiding the bacterial immune system could indirectly boost the human immune system.”
The good, the bad and the bacterium
In addition, the scientists discovered a unique pairing system in which each member of an RNA pair puts the brakes on the other. The researchers think that this system, which regulates both the activation and the silencing of genes in one mechanism, may be common in bacteria.