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Belonging to the RNA virus family Caliciviridae that can infect a wide variety of species, Norovirus is the bane of cruise ships, causing acute viral gastroenteritis (severe gastrointestinal upset characterized by vomiting and diarrhea), with ~20 million annual cases in the US (1) and accounting for ~18% acute gastroenteritis cases worldwide (2).

There are at least two different approaches to probing how noroviruses infect humans.

  • During a norovirus outbreak, why do only some get sick while others remain unaffected, even though they have similar likelihood of exposure?
  • How could a person remain unaffected from norovirus one time and yet get sick another time?

These two questions are really observations and they suggest two different types of processes may be involved in human norovirus infection, one that depends on genetic differences between humans, specifically on blood type antigen differences, and another that depends on gut microbiota, specifically on presence of gut commensal bacteria that express blood type antigens.

During a norovirus outbreak, why do only some get sick while others remain unaffected, even though they have similar likelihood of exposure?

  • Norovirus binds to specific cell-surface carbohydrates called histo-blood group antigens (HBGA) (3, 4).
  • Expressed not just on red blood cells but also on epithelial cells in the gastrointestinal, genitourinary and respiratory tracts, HBGAs can also be secreted into body fluids including saliva (5).
  • Expression of HBGAs varies widely among humans.
    • For e.g., ~20% of Europeans and North Americans have nonsense mutations in the FUT2 gene (codes for a fucosyltransferase enzyme) and as a result, don’t express HBGA on their epithelial cells (5). Such people are characterized as ‘nonsecretors‘ because they lack HBGA secretion in saliva.
    • OTOH, Asian nonsecretors have missense mutations in the same enzyme (6), which leads to small amounts of HBGAs in secretions.
    • Tests on healthy volunteers show that some nonsecretors are resistant to norovirus infection (7, 8).
    • However, even among the secretor phenotype, people with blood group B remained uninfected and asymptomatic in one study (7).
    • Epidemiological data corroborate the connection between FUT2 inactivation and strong but incomplete resistance to norovirus (9, 10, 11, 12). Incomplete implies other factors also contribute to resistance.
  • A combination of FUT2 and ABO blood group system seems to thus influence resistance or susceptibility to norovirus.
  • Different Norovirus strains recognize different HBGAs (4, 13), implying HBGA expression profile of individuals exposed to a particular norovirus would influence their likelihood of getting infected.
  • Thus norovirus strain and human HBGA (and blood group) expression pattern appear to represent a set of ‘keys’ and ‘locks’, respectively, implying that during a norovirus outbreak, people who get sick express cell-surface locks that can be opened by the keys expressed by a given norovirus strain whereas cells of other similarly exposed people who don’t get sick express locks norovirus keys can’t bind and thus they remain uninfected and therefore unaffected (14).
  • More recently, scientists found norovirus also bind other cell-surface carbohydrates, Ganglioside (15; see figure below from 16).

How could a person remain unaffected from norovirus one time and yet get sick another time?

Two possibilities could explain this phenomenon.

  • A person may be resistant to one but not another norovirus strain for reasons already outlined in the previous section, i.e., they express HBGA that one but not another norovirus strain can bind.
  • Presence of specific commensal bacteria in the gut could render a person susceptible to norovirus infection, specifically, presence of HBGA+ gut microbes (Yes, apparently even bacteria can express HBGA).

Norovirus was discovered in 1972 but until 2014 it couldn’t be cultured in human cells using classic cell culture techniques. This has stymied every aspect of its research from basic biology of how it infects cells and replicates to therapy as in drugs that could kill/inhibit it to control as in vaccines that could be effective against it.

  • The big surprise is though norovirus was thought to target Intestinal epithelium cells, the cells that form the gut barrier, a 2014 study (17) found that it instead targets B cell.
  • The other major surprise? The finding that gut microbial flora helped human norovirus effectively target and infect B cells. How? In this study, norovirus infected a human B cell line only in presence of HBGA+ bacteria (See figure below from 18).

How norovirus infects human cells isn’t yet completely understood. Clearly other as-yet unidentified receptors are involved. Meantime, this newly discovered role of HBGA+ gut microbiota in this process suggests a person may get infected one time but not another time, depending on presence or absence, respectively, of HGBA+ bacteria in their gut. Of course, such an idea is purely speculative at present and depends on whether or not HBGA+ bacteria are stable inhabitants of gut microflora.

Bibliography

1. Hall, Aron J., et al. “Norovirus disease in the United States.” Emerg Infect Dis 19.8 (2013): 1198-205. http://wwwnc.cdc.gov/eid/article…

2. Ahmed, Sharia M., et al. “Global prevalence of norovirus in cases of gastroenteritis: a systematic review and meta-analysis.” The Lancet infectious diseases 14.8 (2014): 725-730. https://www.researchgate.net/pro…

3. Huang, Pengwei, et al. “Noroviruses bind to human ABO, Lewis, and secretor histo-blood group antigens: identification of 4 distinct strain-specific patterns.” Journal of Infectious Diseases 188.1 (2003): 19-31. Identification of 4 Distinct Strain-Specific Patterns

4. Tan, Ming, and Xi Jiang. “Norovirus and its histo-blood group antigen receptors: an answer to a historical puzzle.” Trends in microbiology 13.6 (2005): 285-293.

5. Marionneau, Séverine, et al. “ABH and Lewis histo-blood group antigens, a model for the meaning of oligosaccharide diversity in the face of a changing world.” Biochimie 83.7 (2001): 565-573. https://www.researchgate.net/pro…

6. Kudo, Takashi, et al. “Molecular genetic analysis of the human Lewis histo-blood group system II. Secretor gene inactivation by a novel single missense mutation A385T in Japanese nonsecretor individuals.” Journal of Biological Chemistry 271.16 (1996): 9830-9837. Molecular Genetic Analysis of the Human Lewis Histo-blood Group System

7. Lindesmith, Lisa, et al. “Human susceptibility and resistance to Norwalk virus infection.” Nature medicine 9.5 (2003): 548-553. https://www.researchgate.net/pro…

8. Carlsson, Beatrice, et al. “The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII. 4 Norovirus infection.” PloS one 4.5 (2009): e5593. http://journals.plos.org/plosone…

9. Tan, Ming, et al. “Outbreak studies of a GII‐3 and a GII‐4 norovirus revealed an association between HBGA phenotypes and viral infection.” Journal of medical virology 80.7 (2008): 1296-1301.

10. Van Trang, Nguyen, et al. “Association between norovirus and rotavirus infection and histo-blood group antigen types in Vietnamese children.” Journal of clinical microbiology 52.5 (2014): 1366-1374. Association between Norovirus and Rotavirus Infection and Histo-Blood Group Antigen Types in Vietnamese Children

11. Currier, Rebecca L., et al. “Innate susceptibility to norovirus infections influenced by FUT2 genotype in a United States pediatric population.” Clinical Infectious Diseases 60.11 (2015): 1631-1638. Innate Susceptibility to Norovirus Infections Influenced by FUT2 Genotype in a United States Pediatric Population

12. Hutson, Anne M., et al. “Norwalk virus infection associates with secretor status genotyped from sera.” Journal of medical virology 77.1 (2005): 116-120.

13. Tan, Ming, and Xi Jiang. “Norovirus–host interaction: multi-selections by human histo-blood group antigens.” Trends in microbiology 19.8 (2011): 382-388. http://www.ncbi.nlm.nih.gov/pmc/…

14. Carmona-Vicente, Noelia, et al. “Characterisation of a household norovirus outbreak occurred in Valencia (Spain).” BMC infectious diseases 16.1 (2016): 1. https://www.researchgate.net/pro…

15. Han, Ling, et al. “Gangliosides are ligands for human noroviruses.” Journal of the American Chemical Society 136.36 (2014): 12631-12637. http://pubs.acs.org/doi/pdfplus/…

16. Chemical and Engineering News, Stu Borman, Sep 8, 2014. New Ligand For Human Norovirus Could Inspire Treatments For Stomach Flu. New Ligand For Human Norovirus Could Inspire Treatments For Stomach Flu

17. Jones, Melissa K., et al. “Enteric bacteria promote human and mouse norovirus infection of B cells.” Science 346.6210 (2014): 755-759. https://www.researchgate.net/pro…

18. Karst, Stephanie M. “The influence of commensal bacteria on infection with enteric viruses.” Nature Reviews Microbiology 14.4 (2016): 197-204.

https://www.quora.com/Why-do-my-American-friends-get-sick-by-norovirus-every-Thanksgiving-but-Ive-never-seen-a-Russian-citizen-gotten-sick-by-norovirus-in-her-homeland/answer/Tirumalai-Kamala

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