Norovirus
The Agent 
Most outbreaks of nonbacterial gastroenteritis or “stomach flu” in the United States are caused by members of the Calicivirus family. The caliciviruses consist of four groups, of which the noroviruses are the most important human pathogen. Norwalk virus is the best known member of the norovirus group, and it has made headlines as the cause of outbreaks of gastrointestinal illness on cruise ships. Noroviruses were the only identified cause of an outbreak of gastroenteritis among Hurricane Katrina evacuees sheltered in a crowded Houston stadium.
Gastroenteritis is an inflammation of the stomach and the small and large intestines and is associated with vomiting and/or diarrhea. It can be caused by bacteria or by a variety of viruses, including caliciviruses. It is usually not fatal, but the greatest risk is to infants and the elderly and others who are at risk for dehydration.
Norwalk virus was the first norovirus identified as a cause of gastroenteritis following an outbreak of “winter vomiting” at an elementary school in Norwalk, Ohio in 1968. Further investigations revealed that the illness was caused by a small virus that consists of a single strand of RNA, which comprises the genetic material of the virus, surrounded by multiple copies of a single protein assembled into a protective coat that is called the capsid.
X-ray structure of the Norwalk virus capsid, with the inset showing details of the structure of the subunits.
The different colors represent different regions of the capsid protein.
Courtesy: Dr. B.V.V. Prasad
Calicivirus outbreaks often occur in institutional settings, such as child care facilities, schools, nursing homes, dormitories, and cruise ships. Because the virus is so contagious, it spreads rapidly through these environments. The viruses are found in the stool or vomit of infected people. Caliciviruses spread through food that has been contaminated by infected handlers, water or shellfish that has been contaminated by sewage, or through direct contact with an infected person. The caliciviruses that cause gastroenteritis in humans are not known to infect any other animals.
The Problem
Noroviruses are the most common cause of gastroenteritis outbreaks and are estimated to cause 23 million cases in the United States alone each year. Norovirus infection occurs worldwide, and it is a frequent cause of traveler’s diarrhea.
Caliciviruses are classified as Category B bioterrorism agents because they
- are very contagious and can be easily transmitted by water, food, aerosols, and by person-to-person spread
- require only a very low dose to cause an infection
- are highly stable in the environment
Large outbreaks of the disease can cause economic problems and could potentially overwhelm the capabilities of public health, hospital, and military facilities. Furthermore, once a facility becomes contaminated, it is difficult and expensive to eliminate the virus.
There is currently no way to treat calicivirus infections, other than rehydration therapy. Calicivirus infection is also difficult to diagnose. There is no vaccine to prevent calicivirus infection at this time.
The Research
The challenges in calicivirus research are to develop models in which to study the viruses, to develop methods to more easily detect the viruses, and to develop ways to treat and prevent calicivirus infection.
A major hindrance to norovirus research has been the lack of a system in which to grow the virus. Scientists like to have a cell culture system and a small animal model system in which they can study details of how viruses cause illness and use these systems to test antiviral agents. In a step to overcoming this obstacle, Drs. Mary Estes and Robert Atmar of the Department of Molecular Virology and Microbiology (MVM) at Baylor College of Medicine (BCM) and members of their laboratories have developed a mammalian cell culture system in which Norwalk virus is able to replicate (see original article). The availability of this system makes it feasible to test antiviral agents in mammalian cells. In a further study, these researchers were able to demonstrate replication of Norwalk virus RNA that was originally isolated from Norwalk-infected human volunteers following transfer into a mammalian cell system.
Scientists would also like to have additional reagents which recognize noroviruses that would be useful in combating norovirus infections. A collaborative effort among members of MVM is underway to develop molecules, such as antibodies, peptides, and aptamers that specifically recognize noroviruses. These molecules will be explored as potential diagnostics and therapeutics to detect and prevent human norovirus infections. This project is being performed by Drs. Mary Estes, Timothy Palzkill, Robert Atmar , and Dr. B.V. Venkataram Prasad .
A representation of the X-ray structure of the Norwalk virus protease showing details of its architecture
Courtesy: Dr. B.V.V. Prasad
In another project, Drs. Prasad and Estes have been investigating the architecture of caliciviruses. Knowing the structure of a virus and the components that make it up, especially the molecules of a virus necessary for its replication and the parts of a virus that interact with molecules in cells, helps scientists understand how the proteins function during the life cycle of the virus. Information about the structure of virus proteins is also extremely useful in designing specific antiviral agents and for vaccine development. Several years ago, Drs. Prasad and Estes obtained the X-ray structure of the Norwalk virus capsid, the outer protein coat of the virus that encloses the genetic material (see article).Subsequently, these investigators have determined the structure of the Norwalk virus protease protein, a protein that is necessary for the processing of other viral proteins (see article).
In addition to studying the structural details of the virus itself, it is also important to understand exactly how the virus interacts with its cellular targets. This type of investigation can yield valuable information as to how a virus enters cells and starts an infection. It has been known for some time that as much as 20 percent of the population is resistant to infection by Norwalk virus. Susceptibility to Norwalk virus infection was shown several years ago by Drs. Estes, Atmar, and Anne Hutson to be associated with antigens that determine blood type. Using the technique of X-ray crystallography, Drs. Prasad and Estes and their colleagues have now examined the precise interaction between the Norwalk capsid protein and blood group antigens (see article). The antigens for both blood types A and O were found to bind to the same surface-exposed site of the Norwalk virus capsid protein. The binding site is present on the originally identified Norwalk virus but not the form of the virus that is currently circulating on cruise ships. This finding gives the scientists clues as to how the norovirus family has evolved and how the viruses might continue to evolve. The detailed information they have obtained may also be useful in designing drugs to prevent norovirus infection by blocking this interaction.
For more information:
http://www.cdc.gov/ncidod/diseases/submenus/sub_norwalk.htm
http://www.cdc.gov/ncidod/dvrd/revb/gastro/faq.htm
http://www.cdc.gov/ncidod/dvrd/revb/gastro/norovirus.htm
http://www.cidrap.umn.edu/cidrap/content/fs/food-disease/causes/noroview.html
http://www.bcm.edu/findings/vol1/is1/03jan_n4.htm
http://www.bcm.edu/news/item.cfm?newsID=1162