Unraveling the Key to a Cold Virus’s Effectiveness

If there is a champion among contagions, it may well be the lowly rhinovirus, responsible for many of the coughs and sniffles that trouble us this time of year. Rhinoviruses are spectacularly effective at infecting humans. Americans suffer one billion colds a year, and rhinoviruses are the leading cause of these infections.

Scientists have never been sure why they are so effective, but now a team at Yale University may have found a clue. The scientists argue that rhinoviruses have found a blind spot in the human immune system: They take advantage of the cold air in our noses.

In the 1960s, researchers first noticed that if they incubated rhinoviruses a few degrees below body temperature, the viruses multiplied much faster. It was an intriguing finding, since rhinoviruses often infect the lining of the nostrils, which are cooled by incoming air.

In subsequent years, scientists searched for an explanation. “People have taken the virus apart and studied its parts,” said Akiko Iwasaki, an immunobiologist at Yale. “But none of this really added up to explain why the virus replicated faster at a lower temperature.”

Dr. Iwasaki and her colleagues wondered if scientists had been looking at the wrong side of the cold equation. Perhaps the rhinovirus doesn’t adapt in any special way. Perhaps we do a worse job of fighting it at lower temperatures.

To test this possibility, the researchers designed an experiment in which they disabled genes in cells in a dish , then tested how easily the rhinoviruses infected the cells at various temperatures. They chose cells from the airways of mice, since scientists can easily shut off genes in rodents.

But there was a hitch: Human rhinoviruses don’t breed well in mice. Dr. Iwasaki and her colleagues solved this problem by allowing the viruses to mutate and adapt until they grew quickly in their new hosts.

Dr. Iwasaki and her colleagues were then able to observe what happened to the mouse cells when rhinoviruses attacked. At body temperature, the cells responded with a sophisticated defense, sending out warning signals to uninfected cells around them. Those cells prepared an arsenal of antiviral proteins, which they used to destroy the rhinoviruses.

But at a relatively cool 91.4 degrees Fahrenheit, Dr. Iwasaki and her colleagues found, things changed.

The neighboring cells only managed a weak defense, allowing the rhinoviruses to invade them and multiply. This result pointed to an explanation for why rhinoviruses plague humans at low temperatures: In cool conditions, the immune system somehow falters.

To test this explanation, the scientists looked more closely at the chain of proteins involved in defending cells, from the sensors that grab onto a virus to the proteins that act as warning signals. They found that if they shut down genes responsible for making some of those proteins, the cells could no longer defend themselves at body temperature. Rhinoviruses invaded these impaired cells easily whether they were warm or cool.

By infecting the nose, rhinoviruses may escape the immune system by lurking just beyond its reach. “They have found this niche,” Dr. Iwasaki said.

The team published its study  this week in Proceedings of the National Academy of Sciences.

“I found the work to be fascinating and convincing,” said Dr. James E. Gern, a pediatrician at the University of Wisconsin School of Medicine, who was not involved in the study. But he cautioned that rhinoviruses infecting cells in a dish may not behave as they would in, say, a wheezing subway commuter.

“A main problem is that none of the experiments are done in living animals,” said Vincent Racaniello, a virologist at Columbia University who was not involved in the study.

Many other viruses, such as influenza, also infect the respiratory tract. But they specialize in invading cells further down the airway, as far as the lungs, where temperatures are higher than in the nose. Those viruses are known to carry genes that help jam the warning signals that cells use to fight infections.

Scientists also have discovered strains of rhinoviruses that infect the lungs, and they have linked these infections to asthma attacks in children. Dr. Iwasaki suspects that rhinoviruses don’t use a sophisticated signal-jamming strategy to invade these warmer parts of the body. “Perhaps these individuals have impaired immune defenses against the rhinoviruses,” she said.

Dr. Iwasaki is now wondering if other viruses take advantage of cool temperatures to escape the immune system. They may find these refuges not only in the upper airway, but in the testicles, for example, which have to stay cool for sperm to develop normally.

While scientists have long speculated that fevers can be good for us, they haven’t dug into the molecular details explaining exactly why. The new finding suggests that our bodies may trigger fevers to make the immune system fight infections more effectively.

“That’s also one of those questions that there really isn’t a good answer for — why we have fever and how it helps us get rid of pathogens,” said Dr. Iwasaki. “So in both directions, both higher and lower temperatures, we’re excited to explore.”