Eric Wang

Yale researchers found that contracting the common cold could help protect against later infection with the flu.

In the midst of one of history’s largest public health crises, assistant professor of laboratory medicine and immunobiology Ellen Foxman and her team published a paper on the relationship between the common cold and the flu. The paper included data spanning three years and a total of 13,000 patients who entered Yale New Haven Hospital with respiratory symptoms. Foxman and her team found that the spread of the common cold and the flu rarely occurred simultaneously and speculated that there could be some unknown interaction between them.

In order to understand how one virus could interfere with the other, Foxman and her team conducted a study simulating sequential infections of the rhinovirus and influenza A. The rhinovirus is responsible for the common cold, and influenza A is the virus associated with the seasonal flu. Using stem cells to generate tissues like the ones found lining human airways — key targets for respiratory viruses — the group observed that influenza A infection was blocked when the tissue had been previously infected by the rhinovirus. 

“When the common cold virus comes in and grows in the cells forming the lining of the airway, it triggers the general interferon response,” Foxman said. “This involves changes in the levels of hundreds of genes that protect against many viruses, including the flu.”

Foxman and her team found that the resulting lowered risk of influenza A infection tends to last for an average of five days. They attributed the effect to the presence of previously activated antiviral defenses mediated by interferon proteins, which alert the immune system of the presence of foreign invaders.

Anchi Wu MED ’26 GRD ’26, one of the study’s co-authors, explained that the experimental model they used allowed them to observe tissue repair after the first infection.

“This allowed us to study infections sequentially so we could better determine if and how viral interference was indeed happening,” she wrote to the News in an email.

Viral interference is a protective phenomenon whereby earlier viral infections could prevent someone from subsequently contracting other viruses, Wu explained. Even though it is not a novel concept, Wu said that little is understood about the science that underlies it.

“Our current understanding of viral interference’s mechanism involves the innate immune system,” Wu wrote to the News in an email. “This is generally considered nonspecific in what it affects, hence why it is able to defend against multiple types of pathogens.”

According to Wu, examining this phenomenon using an organoid model was an experimental strength, since innate immune responses — the body’s first line of defense against disease-causing molecules — can differ significantly across hosts. The human rhinovirus, for example, does not replicate in mice models, Wu said.

“Because our model more closely mimics the human body’s natural tissue, we were able to better replicate the physiological conditions and immune responses we would expect in a human patient using human viruses,” Wu wrote.

Eleven years ago, the world was grappling with a different pandemic inflicted by the H1N1 subtype of influenza A, popularly known as the swine flu. According to Foxman and Wu, people observed that the virus struck Europe months after original estimates — engendering speculation about how other viruses, such as the rhinovirus, could interfere with H1N1 dissemination.

“The clear starting point of this project [was] the interesting observations from the 2009 flu pandemic,” Foxman told the News.

Both the common cold and the seasonal flu have some degree of annual seasonality. According to the Centers for Disease Control and Prevention, the common cold season is thought to begin in the winter and end in the spring, whereas the influenza season is typically at its most severe during the fall and winter. In 2009, however, the usual wave of rhinovirus infections that occurs at the beginning of the school year seemed to delay the influenza A pandemic, according to Foxman.

Wu pointed out that H1N1 and the rhinovirus peaked at different times during 2009, with rhinovirus incidence climbing before that of influenza. This indicated that some interaction could be connecting these separate outbreaks. Foxman also added that although there was speculation about viral interference in 2009, “no one had a way of testing it — it was just an idea.”

According to Wu, previous studies have also shown that, for some respiratory viruses, simultaneous detection of more than one virus in the same patient is relatively rare. Foxman also explained that more studies are necessary to investigate whether this concept of viral interference could apply to other viruses.

“Even though you can try to assume that things would be the same if you use a different virus, nature is surprising and each virus is a little bit different,” Foxman said. “We would love to try some other combinations of viruses and see if we can predict, from the biology of the virus, whether there would be interference and, if so, how much.”

Professor of laboratory medicine and infectious diseases Marie-Louise Landry, another of the paper’s co-authors, added that even though this particular study specifically focuses on viral interference between the rhinovirus and influenza, early data from the pandemic suggests that SARS-CoV-2 — colloquially known as the coronavirus — could potentially be inhibited by interferon response as well.

“More work needs to be done, but it is hoped that strategies to induce the interferon airway response will be able to contribute to the armamentarium against SARS CoV-2,” Landry wrote in an email to the News.

Foxman explained, however, that the potential use of interferon response in the treatment for the novel coronavirus may be complicated. Despite the molecule’s ease of manipulation in the lab and common use in the treatment of hepatitis, interferon’s mode of action is extremely limited.

She also mentioned that, because of social distancing, other naturally-occurring viruses have not spread as widely during the pandemic as they have in the past.

“This year, we are really disrupting the natural [epidemiological] cycle with our behavior, and also we have a pandemic virus going through,” Foxman added. “People are wearing face masks and that might really decrease the spread of all respiratory viruses.”

Even if it is too soon to tell whether the coronavirus may be curtailed through viral interference, Wu said that it is generally important to study this unexplored area. According to Wu, a better understanding of the mechanisms of viral interference can help predict how future epidemics may interact with each other.

Wu also emphasized that even though this study could have future epidemiological implications, it does not dismiss the importance of respecting current public health guidelines.

“We are still in the middle of the COVID-19 pandemic with no approved vaccine,” Wu wrote. “Wear a mask, wash your hands, maintain social distancing.” 

According to the CDC, as many as 56,000 people die from flu-related illnesses every year. 

Maria Fernanda Pacheco | maria.pacheco@yale.edu

Beatriz Horta | beatriz.horta@yale.edu