The Price of a Sophisticated Immune System

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.