New findings may help better understand how harmless viruses can cause severe disease among patients with weakened immune systems

When a major branch of the mouse immune system is disabled, a normally harmless virus can rapidly mutate into a lethal one, according to researchers at Washington University School of Medicine in St. Louis.

The findings may help clinicians better understand how otherwise harmless viruses can cause severe disease among patients with weakened or suppressed immune systems, including AIDS patients, transplant recipients and patients with autoimmune diseases.

“The virus exploits whatever little crack you give it in mice, so we’re very interested in finding out whether this also occurs in humans with weakened immune systems, ” says Anthony R. French, M.D., Ph.D., an instructor in pediatrics and first author of the study, which will be published in the June issue of the journal Immunity.

Senior investigator for the study is Wayne M. Yokoyama, M.D., the Sam J. Levin and Audrey Loew Levin Professor of Research in Arthritis, professor of medicine and of pathology and immunology and chief of the Division of Rheumatology. Yokoyama is a Washington University physician at Barnes-Jewish Hospital and a Howard Hughes Medical Institute investigator.

“There are many patients in whom the same branch of the immune system that was disabled in these mice is significantly weakened or wholly disabled,” Yokoyama says. “It’s very important for us to understand the processes through which viruses that normally would be no problem for a healthy immune system can become a significant problem for these patients.”

Mouse and human immune systems have two major branches. The innate immune system responds quickly to an invasion but is relatively inflexible. The adaptive immune system can change to continue pursuit of a mutating invader, but it does so slowly.

Researchers in Yokoyama’s laboratory previously found that disabling innate immunity allowed the normally harmless mouse version of cytomegalovirus (MCMV) to kill mice in about a week. In the absence of the fast-acting innate immune system, the adaptive immune system cannot respond quickly enough, and the virus spreads rapidly, overwhelming the mice.

When scientists reversed the experiment for the new study, leaving the innate immune system intact and disabling the adaptive immune system, the mice were initially able to survive MCMV infection. But the virus mutated within three to four weeks, came back and killed the mice.

“It’s important to note that the virus that comes back is not the virus that was originally put in,” Yokoyama says. “MCMV normally produces a protein called M157 on the surface of cells it infects. Natural killer cells, which are part of the innate immune system, can recognize this protein and kill infected cells. But after a few weeks, mutant versions of the virus start appearing, and these viruses don’t produce M157 on the surface of the infected cells, or they alter the protein in some way.”

According to Yokoyama, the virus is exploiting the innate immune system’s greatest vulnerability: its inability to change. Freed from the pressure of innate immune system attacks, the mutant viruses spread rapidly.

“It’s amazing — this is happening during the course of a single infection, not over years of viral evolution,” he says. “We think this could be applied to many other aspects of innate immunity and how pathogens respond to it.”

Mice with normal immune systems develop adaptive immunity to the original virus. How such virus-immune mice would respond to mutated virus taken from the mice with damaged immune systems is still uncertain. Because the mutated virus can slip past the fast-acting innate immune system, French notes, a large dose might prove harmful or even fatal to mice with normal immune systems.

“It’s not clear that this would always be the case, though, because the mutations that enable the virus to evade the innate immune system may weaken the virus in other ways,” French says.

Yokoyama notes that other researchers have shown that a different class of virus, the RNA viruses, can escape from adaptive immunity in a similar fashion. MCMV is a double-stranded DNA virus, though, and this is the first time scientists have seen a DNA virus evade innate immunity through rapid mutation.

Yokoyama, French and colleagues are planning a follow-up study in human patients with weakened immune systems to see if they can detect similar mutations in viruses.

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