When the common cold rips through a household, it can leave a wildly uneven path of symptoms. The same cold-causing rhinovirus that produces barely a sniffle in one person can cause a week of stuffy-nose suffering in the next and in others trigger coughing and trouble breathing that can send them to the hospital.
To understand how these wintertime nuisances unfold, why they can be so variable and how to make them less miserable, researchers at Yale School of Medicine cultivated miniature models of nasal airways. Over four weeks, they grew nasal stem cells into organoids, tiny versions of the interface between our noses and the air — complete with cells that produce mucus or have attached hairlike structures called cilia that pulse in a wavelike rhythm to move mucus and debris.
Then, the scientists infected their nose-in-a-dish with a rhinovirus, a common cause of the cold.
After examining thousands of individual cells, the researchers found that it’s not the virus, but the intricacies of the response in thousands of nasal airway cells that determines whether a cold is quickly quelled or explodes into something more serious.
In a study published Monday in the journal Cell Press Blue, the researchers say the quick production of a protein called interferon by the infected cells kept the rhinovirus in check, allowing it to infect fewer than 2 percent of the cells. When they suppressed interferon, about a third of cells became infected and the rhinovirus proliferated. A different immune sensor kicked in, and molecules related to inflammation increased, mucus production went into overdrive and the cilia slowed their pulsing.
“Part of the reason why their model system is so powerful is it’s reductionist. They’re able to reveal the way that these pathways are either interconnected, or that one can sort of take over in the absence of another,” said Patrick Mitchell, an assistant professor of microbiology at the University of Washington who was not involved in the study.
Sebastian Johnston, a professor of respiratory medicine and allergy at the National Heart and Lung Institute at Imperial College London who was not involved in the study, said that the novelty of the study wasn’t any individual finding, but how it puts the pieces together to illuminate the detailed choreography of how the immune system responds to a rhinovirus infection.
“What it does is put the story together in a very comprehensive and thorough way — using the most modern techniques,” Johnston said. “This is a very nice piece of work, which has got the message just spot on.”
The long quest for a cure for the common cold
It’s no surprise that interferons are key in the initial response to an infection. The idea that the family of proteins that the body releases to fight diseases could be used to cure the common cold first gained traction in the early 1980s, and there was hope that a cure for all viral infections might be around the corner.
But efforts to use interferon as a cure for the common cold have been complicated by side effects and difficulty in timing the interferon early enough in the infection.
“Rhinovirus is a challenging thing to study. It’s probably the most common respiratory virus in humans, but it doesn’t really infect other animals,” said Ellen Foxman, an associate professor of laboratory medicine and immunobiology at Yale who led the work. The models she grows allow her to untangle, cell by cell, how infections unfold and how they are kept in check, yielding hope for treatments.
“The key is how to prime that response to happen,” Foxman said.
Her team hopes to understand what leads to a strong interferon response in some people but not others. She is also intrigued that when interferon response was blocked, the airway cells sensed the virus via the presence of a different viral enzyme, triggering an inflammatory response that could also be a target.
“It causes a lot of mucus production, coughing and sneezing, and mucus production is how the virus spreads,” Foxman said. “When those symptoms happen in the lung, that’s what clogs the airway and when those symptoms happen in the nose, that’s what causes a cold.”
There’s a reason that the cold is such a challenge to solve: Disentangling immune responses to know which ones are beneficial, which ones help control an infection and which ones contribute to severity of symptoms is not straightforward.
“If this was an easy problem to solve, it would have been solved a long time ago. The elegant way the body fights these infections really early, in a really small way before they get big, is not something we can replicate right now,” Foxman said.
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