Competition between respiratory viruses could prevent a “triple epidemic” this winter | Science

Triple threat. Tripledemic. A perfect viral storm. These chilling phrases have dominated recent headlines as some health officials, clinicians and scientists predict that SARS-CoV-2, influenza and respiratory syncytial virus (RSV) could rise at the same time in parts of the northern hemisphere that have relaxed masking, social distancing, and other COVID-19 precautions.

But a growing body of epidemiological and laboratory evidence is reassuring: SARS-CoV-2 and other respiratory viruses often “interfere” with each other. Although waves of each virus can stress emergency rooms and intensive care units, the small clique of researchers who study these virus crashes say there’s little chance the trio will peak together and collectively crush systems. hospital like COVID-19 did at the start of the pandemic.

“Influenza and other respiratory viruses and SARS-CoV-2 just don’t get along very well,” says virologist Richard Webby, an influenza researcher at St. Jude Children’s Research Hospital. “They are unlikely to circulate widely at the same time.”

“One virus tends to intimidate others,” adds epidemiologist Ben Cowling of the University of Hong Kong’s School of Public Health. During the outbreak of the highly transmissible Omicron variant of SARS-CoV-2 in Hong Kong in March, Cowling found that other respiratory viruses “were gone…and they came back in April.”

Unraveling these interferences has not been easy given the number of respiratory viruses – coronaviruses, rhinoviruses, adenoviruses, RSV and influenza are just some of the best known – and the many infections that escape notice. However, recent technological advances make it easier to detect infections in people and to study the behavior of several viruses in the laboratory, in cell cultures or stem cell-derived tissues called organoids. Increasingly, researchers are identifying a cause: the chemical messengers that infected people produce, aptly called interferons.

When a respiratory virus sweeps through a community, interferons can greatly augment the body’s defenses and temporarily erect a population-wide immune barrier against subsequent viruses that target the respiratory system. “Basically, every virus triggers the interferon response to some degree, and every virus is sensitive to it,” says immunologist Ellen Foxman of Yale University, who has explored interference between SARS-CoV-2 and other viruses in a laboratory model of the human respiratory tract.

Rhinoviruses, which cause the common cold, can trigger influenza A (the most common influenza virus). RSV can strike human rhinoviruses and metapneumoviruses. Influenza A can thwart its distant cousin influenza B. “Viral interference has many major health consequences,” says Guy Boivin, a virologist at Laval University who co-authored a study on viral interference earlier this year. .

Still, interference is not a sure thing when multiple viruses are circulating. A household survey of 2,117 people in Nicaragua, for example, found that flu and COVID-19 cases peaked at the same time in February, suggesting “limited viral interference”, the researchers concluded in a statement. preprint. “I see the interference as a small push,” says Aubree Gordon of the University of Michigan, Ann Arbor, a researcher who led the study with colleagues from Nicaragua’s health ministry. “It depends on the immunity of the population and the last circulation of this virus and the vaccination rates against influenza and COVID.”


As early as 1957, two virologists from the National Institute for Medical Research in London reported a convincing mechanism by which one animal virus could knock out another. Alick Isaacs and Jean Lindemann have probed a well-known mystery in virology circles: chicken egg membranes inoculated with inactivated influenza virus cannot then be infected with a live version. Isaacs and Lindemann found that the chicken embryo secreted a chemical, which they called interferon, which explained the interference. Unlike other immune responses – antibodies, for example – that target specific pathogens an animal has seen in the past, this rapid, non-specific response is part of what is known as the innate arm of the immune system. immune.

A decade passed before interference between different viruses in humans received serious attention. Soviet virologist Marina Vorochilova of the Academy of Medical Sciences wondered why live but weakened versions of poliovirus used in vaccines sometimes failed to grow in the bowels of people who received them, failing to trigger protective immune responses. She found that harmless enteroviruses in the intestinal tract seemed to interfere with polioviruses. Vorochilova then conducted extensive field trials of vaccines composed of attenuated enteroviruses. They worked against these intestinal pathogens and surprisingly also avoided several respiratory viruses. His team linked protection against respiratory viruses to increased levels of interferons.

Colliding virus

Tests carried out on people in Scotland who had breathing problems and who sought medical attention reveal peaks and troughs in the prevalence of influenza A and rhinovirus which indicate that the two viruses are likely to interfere with each other .


But few studies have followed the early findings. “If you look at the literature on virology, more than 95% of the studies are based on the study of a single virus,” explains Pablo Murcia, a virologist at the University of Glasgow.

Sporadic epidemiological reports have documented how waves of influenza seemed to crowd out RSV, parainfluenza, and other respiratory viruses. But confounding variables riddled the data. What if, for example, sick children who stayed home after school dodged other viruses? And to confirm which virus had sickened a person, samples had to be grown, which until recently was tedious and often inconclusive.

The 2009 influenza pandemic, caused by a new influenza virus called pH1N1, which recently appeared in pigs, reinforced the study of viral interference. When populations have low immunity to a new strain of influenza, it can circulate widely outside of the winter season, as has happened with pH1N1 influenza worldwide. But groups from Sweden and France, which used the highly sensitive polymerase chain reaction (PCR) tests to detect viral genetic sequences, showed that in those countries, peaks in rhinovirus infections at the end of summer delayed flu peaks until late fall, the normal start of flu season.

More recently, in one of the largest, longest, and most comprehensive studies of respiratory viral infections in humans, Murcia and colleagues used a PCR test that can identify members of 11 viral families to probe nose and throat samples from over 36,000 people who sought care from the National Health Service in Glasgow over 9 years. Among other examples of viral interference, their data clearly showed that rhinovirus and influenza A peaked at different times (see graph above), demonstrating a “negative interaction” between the two viruses, the group concluded. in the December 26, 2019 issue of Proceedings of the National Academy of Sciences.

The following year, Foxman and his colleagues reported finding interference after PCR testing for 10 different viruses in 13,000 respiratory samples from adults who sought care at the Yale New Haven Hospital System. Between 2016 and 2019, about 7% of people tested positive for rhinovirus or influenza A virus, but of those 1,911 samples, only 12 had both viruses, significantly fewer than expected, they reported in The lancet microbe. “It was great to see Ellen Foxman’s article,” Murcia says. “It basically showed similar results to ours, and they’re completely independent studies.”

In the same report, Foxman identified the causal role of interferons. Like normal airways, the organoids his team makes from bronchial epithelial cells trigger immune responses, including secreting interferons. Rhinovirus infection of organoids nearly halted the growth of later added influenza A viruses. Rhinovirus infections led to the expression of a flood of interferon-related genes, the study showed. And when his team treated the organoids with drugs that prevented their cells from mounting an interferon response, the flu viruses thrived.


Now, virus interference researchers are keeping a close eye on the latest respiratory virus to circle the globe. “What interactions could SARS-CoV-2 have with other viruses?” asks Murcia. “To date, there are no solid epidemiological data.” On the one hand, widespread social distancing and the wearing of masks in many countries meant there was little chance of seeing interference in action. “There was almost no circulation of other respiratory viruses during the first 3 years of the pandemic,” says Boivin. Additionally, SARS-CoV-2 has many defenses against interferons, including preventing their production, which could affect its interactions with other viruses.

Yet Foxman has published evidence that, in his organoid model, rhinovirus can interfere with SARS-CoV-2. And Boivin’s team reported that influenza A and SARS-CoV-2 can each block the other in cell studies.

Learning how SARS-CoV-2 and other viruses interfere with each other outside of the laboratory will require prospective studies that closely monitor the same populations over multiple seasons. Cowling now has several relatively small studies underway in Hong Kong, where people repeatedly give blood and respiratory samples whether or not they show symptoms of the disease. It’s slow, he said. “At the moment we don’t have a lot of respiratory infections in Hong Kong,” Cowling adds, noting that masking is still common.

Cowling, Murcia and Foxman all say that lack of funding has limited their abilities to conduct large population studies. Still, they and others remain optimistic that we will soon have the best data yet on the fight between SARS-CoV-2 and other respiratory viruses. “It will be the first real winter where we have a normal mixing pattern of people, and we hope to start seeing some signals,” Murcia said. With several viruses meeting for the first time in 3 years, he hopes to learn that interference remains alive and well and capable of mitigating this winter’s triple threat.

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