There are more than 170 rhinoviruses known to science. These causes of the common cold are found in noses all around you, and while rhinovirus infections tend to yield lots of snot and self-pity, often they cause no symptoms at all.
But if rhinoviruses are relatively benign for most people, infection can be deadly for others.
The last few decades have revealed that rhinovirus infections are behind a staggering number of asthma attacks, and for people with chronic obstructive pulmonary disease (COPD), they are a leading cause of flare-ups, causing breathlessness and coughing that can become dangerous if left untreated.
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The differences in symptom severity don’t seem to be down to the virus itself. “It’s pretty clear now that if you give someone with asthma or COPD a [rhino]virus and then you give the same dose of rhinovirus to a healthy person, the response is quite different,” says Aran Singanayagam, a clinician scientist at Imperial College London who studies respiratory disease.
To get a better understanding of why this happens, scientists have turned to nasal tissue grown in a dish, which they infect with rhinovirus. Now, in a new paper in the journal Cell Press Blue, researchers report that if the tissue’s first-line defenses fail, then what could have been a mild infection spirals out of control. That confirms, with data from individual cells, that differences in the host’s immune system, not the virus’ behavior, are behind these effects.
A detrimental delay
When dish-grown tissue catches a cold, only a handful of cells are actually infected with the virus, says Ellen Foxman, a professor of immunobiology at Yale School of Medicine and an author of the new paper. “We see something very similar to what you would often see in a person with a mild or asymptomatic cold,” she says. “Only about 1% of the cells got infected.”
All cells in the tissue, though, had changed behavior. Molecules released by the infected cells, known as interferons, acted as warning signals to their comrades, causing them to activate their antiviral defenses. As a result, the virus could not spread beyond the first infected cells.
What happened if that interferon signal didn’t go out? Foxman and her colleagues asked. They blocked the warning using a drug, and watched as something completely different unfolded. Before their eyes, the tissue started to ooze mucus, and they found that the cells began to produce signals meant to provoke inflammation. “That’s what you see in people with a cold, or people with asthma or COPD attacks–you see excessive mucus production, and you see those inflammatory cells coming to the lung,” Foxman says.
“The timing really matters,” she continues. “If that response is delayed enough to let the virus replicate and get big enough to trigger other pathways, that’s when you’re going to see the symptoms.”
Indeed, that delay agrees with what’s been seen in other studies, says Nathan Bartlett, a professor at University of Newcastle in Australia and Hunter Medical Research Institute who studies rhinovirus. “We found that if you took cells from an airway that has been chronically exposed to inflammation, there’s been a desensitization,” he says. “It just takes them a bit longer to realize that there’s an infection. And so there’s a delay, we saw, by about 24 hours.”
For a rhinovirus, that’s huge—a 24-hour delay means the virus can double its numbers multiple times before neighboring cells get the message. When cells do finally respond, there’s a lot more virus to fight, and the effects can be much more damaging.
A way forward
This new study, notably, involved only a subset of nasal cells—the dish-grown tissue didn’t have specialized immune cells, for instance, that would be called in when an intact human nose got wind of a virus. However, the study lays out the signals cells send out when the first line of defense is missing, which Foxman hopes will help provide targets for drugs to prevent dangerous reactions to rhinovirus.
The window to intervene in the runaway inflammatory process that seems to kick off in the absence of normal signalling is very small, however. It might make the most sense, speculates Bartlett, to think of a more universal treatment or even, perhaps, a vaccine that could protect the vulnerable before complications arise.
“I’ve seen a number of papers recently that are talking about universal vaccines,” he says, which might stimulate the immune system to provide protection against viruses of all kinds. If such a vaccine is ever brought to the clinic, scientists will be watching to see how it plays out with rhinoviruses.
“We can bring rhinovirus into the conversation now,” he says, “because that’s probably the virus we’re going to be encountering, actually, more than anything. So we better start thinking about it.”
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