Mar. 7, 2003 St. Louis, March 7, 2003 -- A close relative of a common little-understood human virus that causes an estimated 23 million episodes of intestinal illness, 50,000 hospitalizations and 300 deaths each year has been discovered in mice. The finding by scientists at Washington University School of Medicine in St. Louis is reported in the March 7 issue of the journal Science.
Discovery of the new virus, known as murine norovirus 1 (MNV-1), may lead to a better understanding of its disease-causing cousins known as Norwalk viruses, or human noroviruses (HNVs). HNVs cause 90 percent of epidemic viral gastroenteritis worldwide, including those that sweep through cruise ships, nursing homes and military encampments causing debilitating diarrhea and vomiting.
"We know very little about human noroviruses because they cannot be grown in the laboratory or in animals," says study leader Herbert W. Virgin IV, M.D., Ph.D., professor of pathology and immunology and associate professor of molecular microbiology. "This new mouse virus will for the first time allow us to study this important class of human pathogens."
Virgin and colleagues discovered the virus in a strain of immune-deficient mice that were being reared for use in other research. When five of six mice died in one cage, the researchers decided to investigate. They took tissue from the dead mice and filtered and injected it into healthy mice, some of which had normal immunity and some of which were immune-deficient.
The mice with normal immunity remained healthy; the immune-deficient mice died. This indicated an infectious agent was present that healthy mice could resist but that killed immune-deficient mice. Further analysis identified the previously unknown norovirus.
The investigators then went a step further to determine what part of the mouse immune system is most important for fending off the infection.
The original mice had been engineered to lack two proteins: Rag (for recombination activating gene) and Stat1 (for signal transducer and activator of transcription 1).
Animals that lack the Rag do not develop T cells, B cells and antibodies. They therefore cannot recognize specific proteins, or antigens, that are found on viruses, bacteria and parasites. That is, the animals lack so-called adaptive immunity, which begins fighting viruses within a few days of infection.
Animals without Stat1 lack the other half of the immune system, known as innate immunity. Innate immunity kicks in immediately to fight infection, in part by causing cells to produce anti-viral molecules known as interferons. Mice that lack Stat1 cannot respond efficiently to interferon and lose most of their innate immune response. Mice deficient in both Rag and Stat1 have no adaptive and very limited innate immunity.
Virgin and colleagues discovered that mice with Stat1 but lacking Rag survived MNV-1 infection, while those lacking both Rag and Stat1 or Stat1 alone grew sick and died from it. They concluded that a strong innate immune response is essential for fighting off the virus.
"We were surprised to find that T cells or B cells weren't needed to prevent lethal infection by this virus," Virgin says. "Mice without adaptive immunity seem to survive just fine."
Herpes and most other viruses kill mice that lack adaptive immunity, he adds.
The findings also have implications for commercial facilities that develop immune-deficient mice for use in research.
"Our data strongly suggest that infectious agents, including unknown infectious agents, should be considered when interpreting experiments that use immune-deficient mice," Virgin says. "Otherwise, one might conclude that an immune response was due to experimental conditions when in fact it may be due to a new pathogen."
Virgin also suggests that other scientists investigate unexplained deaths in immune-deficient mice.
"It may reveal other new viruses that might be useful for studying human biology and human infectious disease," he says.
Karst SM, Wobus CE, Lay M, Davidson J, Virgin IV, HW. STAT1-dependent immunity to a novel Norwalk-like virus. Science, March 7, 2003.
Funding from the National Institute of Allergy and Infectious Diseases supported this research.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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