In their endless war against the immune system, viruses rapidly evolve new evasive strategies. But scientists have uncovered the first genetic evidence of counter attack by the beleaguered immune defenses: Immune proteins that viruses once exploited have apparently evolved the ability to call in attacks against their former exploiters.
This case of immune proteins turning the table on the invaders may be quite common the researchers think, since genetic evolution appears to race fastest where the fighting is fiercest –in the give-and take battle between pathogens and the receptors that encounter them on the surface of immune cells.
The research led by UCSF scientists will be published online April 11 by SCIENCE (http://www.sciencexpress.org) and will appear in the journal several weeks later.
The discovery comes from a study of a strain of mice able to resist infection by a virus known as murine cytomegalovirus, or MCMV, related to the human cytomegalovirus, smallpox virus, Epstein-Barr and other human viruses.
The key finding involves changes that have apparently occurred in an “inhibitory” receptor – a protein on the surface of natural killer, or NK, immune cells that normally prevents killer cells from launching an autoimmune attack against one’s own tissues. The inhibitory receptor sends a “stop” signal when it recognizes and binds to “self” molecules on normal, healthy tissue, and the signal reigns in the killer cells. Other researchers have found evidence that viruses have evolved the ability to make decoys of these “self” molecules, thereby triggering the stop signal and protecting themselves from immune attack.
The new research shows that in some strains of mice resistant to MCMV, the immune system has adapted by retaining the ability to bind to the virus signal but losing the ability to bind to self molecules. As a result, the former inhibitory receptor has become an “activating” receptor and calls in the immune army against the virus. The tables have been turned, and the viral subversion has been countered.
“These changes probably took place thousands of years ago, yet actually fairly recently in terms of evolutionary time,” said Lewis Lanier, PhD, UCSF professor of microbiology and immunology and senior author on the paper. “When we first found the activating receptor that binds to the viral protein and destroys it, we thought, ‘Why hasn’t the virus evolved a way to get rid of this protein?’ That’s when we started to wonder if the receptor was an adaptation of the immune system to the arms war – a counter attack to the virus’ ability to exploit the inhibitory response,” he said.
In their research, the scientists used a panel of mutant viruses to identify a single gene responsible for the activating receptor in the MCMV-resistant mice strain. Mice lacking that single gene were no longer protected and were susceptible to the virus.
Most mice lack the gene that provides resistance to MCMV, so it is probably a relatively recent development, the scientists reason. They suspect the activating receptor evolved from the inhibitory receptor because the two proteins are about 95 percent identical.
The receptor is one of many, both inhibitory and activating, encoded by the Ly49 family of genes. Their functional counterparts in humans are called KIR (Killer cell Ig-like receptors). As in the Ly49 family in mice, the KIR receptor family has inhibitory receptors that recognize self molecules on normal host cells to prevent autoimmunity, and also deploy activating receptors, suggesting that the same strategy is operational in humans to counter viral infections. Besides smallpox and Epstein-Barr, the human cytomegalovirus is related to the herpesvirus that causes Kaposi’s sarcoma.
It had long seemed a paradox to researchers, Lanier says, that inhibitory and activating receptors could be so similar. With receptors involved in absolutely opposite functions -- activating the immune defenses versus keeping the army shut down – the organism runs the risk of triggering the wrong system, which could have disastrous consequences. This had led to the suggestion that the activating receptors had evolved from the inhibiting receptors to destroy invading pathogens.
Both gene families show “remarkable genetic diversity within the population,” the authors state. Other research has suggested that selection by pathogens might drive the evolution of these receptors. In fact, says Lanier, these might be the fastest evolving genes in humans.
Lanier says his group now is working with colleagues to determine the crystal structure of the activating and inhibitory receptors as they are binding both to the proteins of the immune system and to the viral protein. They would like to see just where the evolution of structure has occurred that allows the evolution of function.
Lead author on the SCIENCE paper is Hisashi Arase, PhD, A UCSF postdoctoral scientist in Lanier’s lab. Co-authors are Ann Hill, PhD, professor of molecular microbiology and immunology at the Oregon Health Science University; Ann Campbell, PhD, professor of microbiology and molecular cell biology at Eastern Virginia Medical School; and Edward Mocarski, professor of microbiology and immunology at Stanford University.
The research was supported by the National Institutes of Health.
Journal
Science