Norovirus and the Innate Immune System

Abstract & Commentary

Synopsis: Data from a murine model indicates the innate immune system is critical to control of Norovirus infection.

Source: Karst SM, et al. STAT1-dependent innate immunity to a Norwalk-like virus. Science. 2003;299:1575-1578.

There are many beautiful discoveries in science. They are more beautiful when they integrate into an emerging problem, such as those we recognize now as emerging infectious disease. Several newly emergent viruses are causing havoc in the world. Humans seem to have limited innate immunity to many of these newly emergent viral pathogens, notably West Nile Virus, noroviruses, and novel coronaviruses that cause severe acute respiratory syndrome (SARS). The intestinal misery caused by Norwalk-like caliciviruses may be self-limited in days, suggesting that innate immunity may be more operative than acquired immunity. Or could norovirus infections have some lasting consequences?

With some serendipity, I suspect, Karst and colleagues at Washington University in St. Louis have recovered a new murine norovirus from the brains of mice deficient in a function known as signal transducer and activator-1 of transcription (STAT-1). They called the new virus Murine Norovirus 1 (MNV1), and they showed through phylogenetic analysis of the viral capsid protein that MNV1 was a norovirus that was relatively unrelated to other noroviruses. Note that the norovirus group is 1 of 4 groups in the Caliciviridae. Of the other 3 groups, Lagovirus, Vesivirus, and Sapovirus, only the last one along with norovirus is pathogenic for humans.

The research group next asked the question of whether mice lacking innate immune function would be more susceptible to MNV1. Well, Karst et al have some very special mice indeed, not only those lacking STAT-1 function but also those lacking recombination-activating genes (RAG2) and those lacking both the interferonab and the interferong receptors. They used these specifically immune-deficient mice to define the immune window of opportunity required for pathogenicity. MNV-1 causes encephalitis, meningitis, cerebral vasculitis, pneumonia, and hepatitis in susceptible animals.

Mice deficient in RAG alone were not killed by MNV-1 but the animals were persistently infected in feces and multiple visceral organs, thus suggesting that B and T cell- dependent adaptive immunity were not necessary for protection from lethality. Mice lacking either interferonab receptors or the interferong receptors were not killed by MVN-1 but mice lacking both were 10,000 times more susceptible to MVN-1, showing that interferon protection is central to innate immunity and that interferonab and the interferong receptors can "compensate" for each other.

The central immune response, however, involves STAT-1 and mice that were STAT-1 deficient were very susceptible to infection. An intact STAT-1 response would prevent lethal infection. When the organs of wild-type mice were compared to STAT-1-deficient mice, the wild-type mice handled the infection like asymptomatically infected humans. Surprisingly, 1 day after inoculation, wild-type mice had viral RNA in liver, intestine, and spleen but not other organs. In the same experiment, STAT-1-deficient mice had MNV1 RNA in multiple organs and tissue injury at 3 and 7 days, suggesting widespread infection associated with STAT-1 deficiency. (To see chart, click here.)

Comment by Joseph F. John, Jr., MD

The medical sciences are becoming very sophisticated, as evidenced by the excellence of this article. Not only did Karst et al discover a new norovirus, but also found how it affected normal and immunodeficient mice. The take-home point is that 1 small deficiency in the viral-defense activation system—1 kinase in that system—can lead to persistent infection. That infection would ordinarily go undetected since the causative agent had heretofore not been identified. They also found that what may seem like primarily an intestinal infection may actually be affecting multiple internal organs. How many other unidentified pathogens lurk in the guts of mice or men remains to be determined.

Mammalian defense systems must respond very quickly to agents like noroviruses, as shown by the Science article. Once the interferon system is fired by the virus, those signals from the interferons trigger intercellular responses from molecules like STAT-1 that in turn trigger a nonspecific antiviral response. In the case of the mouse, and probably humans, that response, if absent, results in severe multisystem infection. Such a small defect results in uncontrolled infection that even delayed cellular and humoral responses would not control.

In what seems to be a totally unrelated article, a group of family practitioners from the Carolinas Medical Center in Charlotte tried to answer an old question of the value of multivitamin and mineral supplements on a broad host of infections.1 Barringer and associates studied only type 2 diabetic patients, but their findings may be more generalized. They gave the multivitamins and mineral supplement (or placebo) to 130 participants for 1 year. The infection incidence was 73% in the placebo group and only 43% in the treatment group. The infections inhibited were primarily milder, respiratory tract and influenza-like illness, but the differences between placebo and treatment groups were, in the words of Barringer et al, dramatic. To that conclusion I agree and support that their findings deserve a larger trial. Perhaps as we study the effect of STAT-1-like activation in humans, we may find that nonspecific medication like vitamins facilitate this early response defense.

Dr. John is Chief, Medical Subspecialty Services, Ralph H. Johnson Veterans Administration Medical Center; Professor of Medicine, Medical University of South Carolina, Charleston, SC.

Reference

1. Barringer TA, et al. Effect of a multivitamin and mineral supplement on infection and quality of life. Ann Intern Med. 2003;138:365-371.