Susceptibility to Norovirus Might Depend on Blood Type

April 10, 2024

Picture this: you and your friend are sharing a vibrant fruit plate from the buffet on a once-in-a-lifetime cruise. The sun is shining, and the fruit is delicious.

Transmission electron micrograph image of norovirus particles
Norovirus is the leading cause of gastroenteritis worldwide.
Source: U.S. CDC
The fun stops for you 12 hours later, when you are overtaken by bountiful bouts of vomiting and diarrhea paired with nausea and stomach pain. Was it the fruit? It was. Clinging to that fruit were a few particles of…norovirus. The leading cause of gastroenteritis worldwide, this virus—colloquially known as the “cruise ship virus” for the outbreaks it triggers on those vacation vessels—is one of the most contagious pathogens there is.

But the friend who helped you devour the fruit is suspiciously fine. This seemingly unfair turn of events is not because you’re (totally) unlucky. It’s also because of biology.  

Norovirus: "The Perfect Pathogen"

To understand why your friend walked away from the buffet unscathed, and you were sequestered in your bathroom for 3 days, it’s useful to understand the virus that started it all.

For norovirus (a small RNA virus) to cause disease, it must be ingested. This can happen if someone consumes food or drink contaminated with the virus or touches a contaminated surface before touching their mouth. Norovirus lacks the fragile envelope that sometimes shrouds viruses (e.g., SARS-CoV-2, influenza). With just its hearty protein shell—the molecular equivalent of a bullet-proof vest—norovirus can withstand various stressors, from high temperatures to certain disinfectants (the CDC recommends using a bleach solution to rid surfaces of norovirus).  

The ability to persist in harsh environments helps the virus survive the hostile conditions of the gut. However, this also makes it hard to get rid of (it can hang out on surfaces for weeks) and easy to spread. What’s more, it  takes fewer than 100 viral particles to cause disease, and some genotypes of the virus—particularly those that frequently cause outbreaks—mutate quickly. The high evolution rate of norovirus hinders formation of long-lasting immunity against the pathogen, and immunity is generally considered short-lived (though studies vary about the precise duration, with estimates ranging from months to years).  

It is characteristics like these—a rapid evolution rate, waning immunity, high transmissibility and low infectious dose, among others—that have prompted some scientists to call norovirus “the perfect human pathogen.” 

Why Are Some People More Susceptible to Norovirus? It’s in Their Blood

But while the virus has no shortage of susceptible hosts (it causes 685 million infections worldwide every year), there are people who some norovirus types simply can’t infect. The reason is linked to blood type.

On the surface of epithelial cells and red blood cells, and floating in secretions like saliva, are molecules called histo-blood group antigens (HBGA). The structure of these molecules determines blood type according to the ABO system; enzymes called fucosyltransferases tack short sugars onto a precursor carbohydrate molecule to create the H antigen, which can be further modified into A and B antigens (for people with type O blood, the H antigen remains unmodified). One such enzyme, FUT2, is mainly expressed in epithelial and mucus-secreting tissues; HBGAs controlled by FUT2 are found on the surface of these tissues, and also as free-floating molecules in blood, saliva and milk. In some cases, people harbor mutations in their fut2 gene that render their FUT2 enzyme inactive—these people are known as “non-secretors,” as they do not secrete HBGA in their mucosa (including the intestine).

 Diagram of ABO blood groups and the antibodies present in each.
Susceptibility to norovirus is tied to HBGA secretion status.
Source: InvictaHOG/Wikimedia Commons

What does this have to do with norovirus? It turns out HBGA expression in the small intestinal mucosa is important for the virus to initiate infection. Specifically, the virus’s capsid protein binds to the H antigen, and variations thereof, to attach to and/or enter the cell (scientists are still a bit fuzzy on these early dynamics of infection). In secretors, this isn’t a problem. In non-secretors, however, the virus might be out of luck.

Note “might” be out of luck: while secretor status is a key determinant of susceptibility, there is nuance to how protective it is. There are 10 genogroups of norovirus, branching further into numerous genotypes. While non-secretors are presumably resistant to some genotypes (including GII.4, which is widespread and often responsible for outbreaks), it does not mean they are protected from all of them. Different norovirus types have different affinities for HBGA and may bind other antigens on the intestinal surface that non-secretors do express. Not all secretors may be equally susceptible, either. A 2005 study suggested that presence of HBGA type B correlated with a lack of susceptibility to norovirus, specifically genotype 1, though a 2020 meta-analysis suggested that blood type A, B and AB do not affect susceptibility. However, in that same analysis, blood type O was tied to increased risk.

Whether or not a person contracts norovirus is thus an interaction between host and viral genotype. In the case of the opening example with the fruit, the person who became ill—a secretor—harbored the cellular markers needed for the virus to establish infection. For the person who remained healthy, the virus may have been a genotype that they (a non-secretor) were able to circumvent.

It's Also in Their Microbiome

There’s also more to the story than secretor status alone. Given norovirus is a gastrointestinal pathogen, the fact the gut microbiota has some role to play is not unexpected. Notably, some gut bacteria produce molecules on their surface that look a lot like HBGA. Because of this, norovirus can bind these bacterial structures, which, based on in vitro studies, has important implications for viral replication. For instance, for norovirus to infect B cells, HBGA-expressing gut bacteria must be present; another study showed that HBGA-like bacterial structures protect the virus from heat stress, and potentially other stressors too. While the “why” underlying these interactions is not clear, they suggest microbiota composition influences norovirus infection. 

Compounds associated with microbial metabolism (bile acids) have also been linked to norovirus replication and facilitate binding to HBGA. Moreover, interactions between the microbiota and host can shape the immune response to modulate norovirus infection dynamics and duration.

Preventing Norovirus Infection

Norovirus is often associated with gastroenteritis outbreaks on cruise ships, in part because close living conditions and shared dining quarters on those ships facilitate spread of the virus. But outbreaks also happen every year in the broader population, particularly between November and April. Scientists point to a conglomeration of host, viral and environmental factors that drive these outbreaks. For example, scientists recently found that outdoor absolute humidity predicts the start of epidemics caused by GII norovirus: as AH goes down, norovirus cases go up, perhaps because aerosolized droplets containing the virus travel farther in such conditions.

Diagram of norovirus cases in U.S. from March 2022 to March 2024
Norovirus infections peak every year between November and April.
Source: U.S. Centers for Disease Control and Prevention

Easing the infection burden of norovirus—at any time, but especially during peak infection season—is a priority. While there is not yet a vaccine for norovirus, there are several candidates in the pipeline. These include an mRNA vaccine and virus-like particle vaccine, the latter of which has shown promise for preventing moderate-to-severe cases of acute gastroenteritis from norovirus infection in phase 2 clinical trials. Vaccines would be particularly beneficial for those who are vulnerable to serious infection (those who are young, immunocompromised or are part of the elderly population).

In the interim, however, avoiding infection requires being vigilant about tried-and-true prevention tactics. Practices like handwashing, handling and preparing food safely (e.g., heating above 140°F) and using disinfectants, such as bleach, that can kill the virus (especially if you or someone around you has or had norovirus) are key.

If you do happen to come down with a case of norovirus infection, the best course of action is to stay hydrated, avoid contact with others (and don’t prepare food for them), wash your hands and clean your surroundings diligently and wait it out—the infection will run its course.

And, when it does, perhaps steer clear of the fruit at the buffet.
Check out this next article to learn about the myths, policies and best practices for disinfecting the home.

Author: Madeline Barron, Ph.D.

Madeline Barron, Ph.D.
Madeline Barron, Ph.D. is the Science Communications Specialist at ASM. She obtained her Ph.D. from the University of Michigan in the Department of Microbiology and Immunology.