Gastro-causing virus needs bile to infect cells

Inflicting nasty nausea and abominable abdominal cramps, gastroenteritis-causing norovirus is awful in real life – and awfully hard to study in a dish in a lab.

But research into the virus, at least, looks as though it’s about to get less painful. A team from Houston, Texas grew intestinal cells in a manner that more closely mimicked a real human gut, and found many strains of the virus needed bile to invade and replicate. They reported their work in the journal Science.

The human norovirus is the most common cause of food-borne gastroenteritis in the world. For most, the vomiting and diarrhoea it brings tend to dissipate in a day or two. In young, elderly and immune-compromised patients, though, it can be lethal.

And despite the virus first being visualised in 1972, when it was snapped by an electron microscope that could pick out the nano-sized particles, scientists since have had trouble unravelling its mechanisms.

The norovirus spreads like wildfire through a workplace or school but stubbornly refuses to infect cells in a laboratory.

The problem, biologists suspected, is that cells in a dish don’t really reflect how cells work in a body. Often just a couple of cell types are grown in a 2-D film, which lack interactions with other cells and molecules found in the body.

And there are many genetic groups, or genotypes, of norovirus, each of which has multiple strains.

So to better understand how cells lining the intestinal wall are invaded by norovirus, Baylor College of Medicine microbiologists Khalil Ettayebi, Sue Crawford and colleagues grew organoids – blobs of tissue grown from intestinal stem cells.

They comprised enterocytes – which line the intestinal wall – alongside other cells such as mucous-excreting goblet cells and antimicrobial Paneth cells.

When the team washed the most common genotype of norovirus GII.4 over the organoids, the virus did, in fact, infect some of the cells.

But when they added bile – a fluid produced by the liver and stored in the gall bladder that helps break down fats – norovirus infection skyrocketed. And it wasn’t just the case for GII.4 norovirus – all strains tested happily wriggled into enterocytes and started replicating.

The more bile, the more the virus replicated.

The virus, the researchers noted, only targeted enterocytes, largely ignoring the other cells in the organoids.

To see if bile boosted infection by affecting the virus or enterocytes – or both – the researchers performed a neat experiment. They bathed GII.3 norovirus particles, which needed bile to infect intestinal organoids, in bile before mixing with organoids.

Conversely, they also exposed some organoids to bile before the GII.3 norovirus.

They found bile-treated organoids were readily infected with non-treated GII.3 virus, but treated GII.3 particles couldn’t make their way into non-treated organoids. This means bile acts on the intestinal cells, not the virus.

Next, the team wants to determine which component of bile supports norovirus infection. Its discovery could not only help develop new diagnostics and therapeutics, but microbiologists will be able to work on the pesky virus in the lab and unlock more of its secrets.