Calicivirius Norovirus

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Noroviruses are RNA viruses that tend to cause gastroenteritis in a range of species, including humans. They have been labeled the “perfect pathogen” and “the Ferrari of viruses” because of their ability to evolve rapidly and spread at high rates. The physical symptoms of noroviral illness are commonly vomiting and diarrhea, which is the principle mode of viral shedding. Other symptoms include myalgia, stomach cramps, and headaches.

Classification

Noroviruses were first identified in 1972, following the initial 1968 outbreak in Norwalk, Ohio, where the name originates. Originally called “Norwalk-like viruses,” norovirus strains are grouped into the Caliciviridae family. The virus itself has been classified into 40 different strains, which has been further divided into genomic groups, I-V. I, II, and IV are known to be pathogenic in humans, with GII being the most common in massive breakouts. Specific strains are usually named after the location of their outbreak such as GII.4 Sydney or Snow Mountain virus.

Genome Structure

The norovirus genome is an approximately 7.5 kb, plus-sense, single stranded RNA that contains 3 Open Read Frames (ORFs). ORF1 constitutes nonstructural protein synthesis, and is cleaved by virus protease 3C into 6 proteins that are used in RNA polymerase and other essential cell functions. ORF2 encodes capsid proteins, along with protruding domains (P1 and P2 and shell S). It is believed that the protruding domain plays a significant role in lethality. These arch-like protruding structural proteins are grouped into what is known as VP1 (viral protein 1), which is the main binding site to histo-blood group antigens HBGA. P1 and P2 sites are crucial for cell interactions and immune recognition, because it protrudes from the surface of the capsid. The protruding groups are also considered extremely variable, especially the P2 region. Variation rates between members of the same genogroup are between 45-61% and within genotypes at a rate of 14-44% (Zheng). This is alarming because of the rate of evolution occurring in areas most common for immune response will make permanent immunization (like polio) unlikely. ORF3 contains a basic protein sequence that codes for a small capsid protein, and is important for VP1 stability and interaction with genome RNA during virion formation. It is contested whether ORF3 or ORF2 is more variable, but there is definite consensus that this segment of the genome displays greater change over time.

Evolution and New Strains

Since it is understood that the protruding regions of the Norovirus are extremely variable, research on the P2 region has accelerated our understanding of the evolution of human strains. Since the protruding regions are interacting with HBGAs, evolution rates are extremely centralized on this sequence specifically. It has been found that the carbohydrate binding sites used in HBGA attacks are evolving rapidly, and is creating a strong immune-driven selective force (Rocha-Pereira). It is through the binding of HBGA sites that norovrius manages to enter the epithelial cells of the GI tract. A common term in the explanation of this selectivity is herd immunity, which is the result of a significant portion of a population developing immunity to a specific pathogen and passing it on to offspring. In the case of the norovirus, this exertion of a strong selective pressure on a small and highly variable section of RNA code can cause a new outbreak every 2-3 years. This leads to a term known as “epochal shifts” which track the antigenic shift that occurs regularly. This is identical to the pathogenicity patterns of seasonal influenza, which also undergo immune-driven selection. It is suggested that evolution in noroviruses occur in spurts, usually in response to the threat of human immunity. A study on frozen fecal samples from the 1970’s showed a nucleotide substitution rate of approximately 4.3 x 10-3 per site per year (Bok et al.). This relatively high rate of evolution can definitely be linked to the diversity of protruding sites, especially P2. Because the genome is positive sense, the rate of translation into viral proteins is expedited greatly and is likely a culprit in the virus’ rapid proliferation. This simplicity means anti-noroviral drugs will have to target the RNA directly after it has been injected into the host cell.


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