Norovirus: We may have misunderstood how common gut viruses spread

Norovirus lives in the gut – but mouse studies suggest it may also survive in salivary glands, and the discovery implies there are additional measures we could take to limit infections

By Carissa Wong

Three gut viruses, including norovirus, can spread through saliva in mice. The discovery – coupled with the finding that norovirus can be grown in human salivary gland cells – might encourage new recommendations for minimising infections, and eventually may lead to new antiviral treatments.

Norovirus, rotavirus and astrovirus are known to infect the gut, where they lead to vomiting, diarrhoea and abdominal discomfort in more than 1.5 billion people globally each year. We already knew these viruses could spread through the faecal-oral route – for instance, without adequate handwashing, tiny particles of faecal matter from an infected person may find their way into a non-infected person’s food.

“These viruses were called gut viruses because they were thought just to replicate in the intestine, shed into the faeces and then that faeces would be passed on to another individual through the oral route,” says Nihal Altan-Bonnet at the National Institutes of Health in Maryland.

As a result, handwashing and cleaning surfaces are considered the best ways to prevent gut viruses spreading.

“Now we looked into the salivary glands, and there we saw a huge amount of viral replication, at levels – pound for pound – as much as the intestine. This was really surprising to us [because] people assumed these viruses don’t spread through the saliva,” says Altan-Bonnet. “This suggests we should put in measures like wearing masks to contain gut virus outbreaks, similar to how we have treated covid-19.”

In a series of experiments, Altan-Bonnet and her colleagues orally infected mouse pups with mouse versions of the three gut viruses, which revealed that the rodents’ salivary glands can act as a reservoir for the viruses to grow.

The team also discovered that infected suckling pups could transmit the virus to the mammary glands of a mother mouse within 24 hours of feeding. The resulting infection is localised to the mammary gland – the mother shows no disease symptoms, says Altan-Bonnet. But an uninfected pup could then catch the virus from the infected mammary gland during suckling.

What’s more, the researchers detected a surge in antibodies in the mammary glands of the adult mice 72 hours after being infected by the pups. This coincided with a drop in the amount of virus in infected pups’ intestines, suggesting that mammary gland infection could generate antibodies in the milk to help clear infections in the suckling pups.

“After about three days of nursing their pups, we start to see the pups’ infections begin to subside, which correlates with the surge in antibodies. It’s suggestive that this very rapid immune response by the mother, after the [pup] infects the mother’s breast, can help clear the [pup’s] infection,” says Altan-Bonnet.

“The fact that mothers rapidly produce protective [antibodies] for their pups when their mammary gland is infected [may be] a fantastic evolutionary response to protect their young,” says Sarah Caddy at Cornell University in New York, who wasn’t involved in the study.

The researchers then extended their work and discovered that human strains of norovirus could be easily and cheaply grown in human salivary gland cells. The discovery is significant because, before now, the virus wasn’t easy to grow in the lab. As a consequence, it has been difficult to develop therapies, which is partly why no vaccine or antiviral therapy against norovirus currently exists.

“Having a better way to culture noroviruses is a kind of holy grail,” says Altan-Bonnet. “We also showed that human salivary cell lines, which are relatively easy and inexpensive to grow, could be excellent models to propagate these viruses, providing model systems in which to test antivirals or produce virus to make vaccines.

“This work is really interesting and important,” says Caddy. “We have known for 20 years that the carbohydrate receptors for norovirus are present in saliva, but no one has convincingly shown this is important for virus transmission until now.”

Next, the researchers hope to investigate whether the viruses can spread through saliva in humans.

“Ultimately, mice are not people. We can hypothesise that the same salivary transmission occurs in human-specific gut viruses, but definitive proof has not yet been shown,” says Caddy.

Journal reference: Nature, DOI: 10.1038/s41586-022-04895-8

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