A Fight With The Flu Could Help Control COVID-19
IRP Mouse Study Reveals Factors That Influence Pandemic Virus’ Replication in the Lungs
New IRP research shows that prior experience with a variety of lung ailments, including the flu and asthma, suppresses replication of the virus that causes COVID-19.
Tuberculosis, the flu, a staph infection, asthma — you’d think all these ailments could only be bad news for the lungs. However, if they don’t get out of control, they might actually turn out to have an unexpected benefit. A new IRP mouse study suggests that a recent bout with these illnesses might prime the lungs to keep a lid on a COVID-19 infection.1
One of the most perplexing aspects of the COVID-19 pandemic was the huge variation in individual experiences with the disease. Despite the incredibly infectious nature of the virus that causes it, SARS-CoV-2, many people never got sick at all, or at least never showed symptoms. For those who showed symptoms, they ranged wildly, mild for some and life-threatening for others.
Naturally, this perplexed scientists like IRP Stadtman Investigator Katrin Mayer-Barber, Ph.D., who studies how the immune system responds to infections. However, studies seeking answers are difficult to do with human patients, and the animal models scientists use for experiments differ from people in more than just the obvious ways.
“Our experimental mice are kept in a clean environment, but in the real world mice get infections and they’re not that clean, so the fact that we perform our experiments in extremely clean animals always made me wonder,” Dr. Mayer-Barber says. “People get exposed to seasonal flu all the time, for example. Our animal models are usually protected from all these exposures that we experience on a daily basis as humans.”
This problem is particularly top-of-mind for Dr. Mayer-Barber, who co-led a 2014 study showing that mice that recently fought off a bout of the flu experienced much worse tuberculosis infections in their lungs.2 More recently, her lab discovered that a prior exposure to tuberculosis reduced the ability of the SARS-CoV-2 virus to replicate in the animals’ lungs.3
Dr. Mayer-Barber’s lab primarily studies the bacteria that cause tuberculosis (pictured here), but recent findings have led her team to expand their work to other lung diseases as well.
To expand on that more recent discovery, Dr. Mayer-Barber’s lab wanted to delve into other conditions besides tuberculosis that cause an immune response in the lungs. In the new study, her team — lead by IRP postdoctoral fellow Paul J. Baker, Ph.D. — looked at levels of SARS-CoV-2 in the lungs of infected mice months after a tuberculosis infection, several weeks after exposure to the flu, or a few days after successfully fighting off the Staphylococcus aureus bacteria responsible for staph infections. The researchers also exposed other mice to substances that induce an asthma-like state in the lungs a few days before exposing them to SARS-CoV-2.
“Because tuberculosis is a chronic disease caused by a very hardy bacterium, we thought maybe this ability to suppress SARS-CoV-2 is unique to that kind of bacteria, so we decided to look at another bacterium that is known to infect the lungs, which is staph,” Dr. Mayer-Barber explains. “It’s a fundamentally different kind of bacteria — it gets cleared very rapidly in the lungs of mice. And then of course we wanted to know if it’s just bacteria, so we tried a virus like the flu. Lastly, we wondered if it has to be a replicating bacteria or virus, or if it could also be just inflammation without an infection, like asthma.”
It turned out that each one of those ailments helped mice suppress replication of SARS-CoV-2 in their lungs better than mice that had never tangled with any them. What’s more, mice exposed to a substance that activates ‘toll-like receptors’ (TLRs), which play an important role in immune responses, one week before exposure to SARS-CoV-2 also controlled the virus better. However, this protective effect was short-lived, as it was not observed when the mice had their TLRs stimulated 7 weeks before encountering SARS-CoV-2.
Dr. Katrin Mayer-Barber
Additional experiments revealed that TLR stimulation boosted the presence of certain types of immune cells in the animals’ lungs, as well as levels of several immune system signaling molecules called cytokines. In addition, substituting TLR stimulation for pretreatment with one of three such cytokines — IL-1, TNF-alpha, or a ‘type-1 interferon’ called IFN-beta — conferred similar protection as prior TLR stimulation. Dr. Mayer-Barber was particularly surprised to see that pretreatment with IL-1 or TNF-alpha could suppress replication of the virus even in mice lacking a gene that allows type-1 interferons like IFN-beta to exert their effects.
“Type-1 interferons are really important for antiviral responses, so we of course looked at those,” Dr. Mayer-Barber says. “IL-1 and TNF-alpha are not as well characterized to be antiviral, so it was really interesting that we found they promote antiviral immunity in the lungs independently of type- I interferons.”
“The IL-1 part was especially exciting,” she adds. “IL-1 is often not associated with antiviral responses — it’s thought to be more involved in bacterial responses — so now we have a pathway that is typically not associated with antiviral immune responses being able to control those responses.”
Among the many intriguing implications of the new findings is a possible explanation for why people with asthma fared better during COVID-19 than many doctors and scientists expected.
Ultimately, the results of the study could help explain why some groups of people — perhaps counterintuitively — fared better during the COVID-19 pandemic than others. Scientists initially thought people with asthma would be more vulnerable to severe illness, for example, but support for that theory has been mixed. And although it’s not entirely clear how levels of SARS-CoV-2 replication in the lungs are related to symptoms later on in the disease’s course, there is reason to believe that the two are linked, so better understanding the factors that affect early viral replication may lead to new ways to curb symptoms.
“This reveals an area that people don’t think about a lot,” Dr. Mayer-Barber says. “We focus so much on what happens after exposure, but really the whole premise of this study is to show we need to pay attention to whether the virus can fall on fertile ground in the lungs and what creates that fertile ground.”
“It would be pretty cool,” she adds, “if we could figure out what it is that makes some people a bit more resistant and use that to figure out ways to boost the natural immunity in the lungs.”
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References:
[1] Baker PJ, Bohrer AC, Castro E, Amaral EP, Snow-Smith M, Torres-Juárez F, Gould ST, Queiroz ATL, Fukutani ER, Jordan CM, Khillan JS, Cho K, Barber DL, Andrade BB, Johnson RF, Hilligan KL, Mayer-Barber KD. The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication. Sci Immunol. 2024 Dec 6;9(102):eadp7951. doi: 10.1126/sciimmunol.adp7951.
[2] Redford PS, Mayer-Barber KD, McNab FW, Stavropoulos E, Wack A, Sher A, O'Garra A. Influenza A virus impairs control of Mycobacterium tuberculosis coinfection through a type I interferon receptor-dependent pathway. J Infect Dis. 2014 Jan 15;209(2):270-4. doi: 10.1093/infdis/jit424.
[3] Baker PJ, Amaral EP, Castro E, Bohrer AC, Torres-Juárez F, Jordan CM, Nelson CE, Barber DL, Johnson RF, Hilligan KL, Mayer-Barber KD. Co-infection of mice with SARS-CoV-2 and Mycobacterium tuberculosis limits early viral replication but does not affect mycobacterial loads. Front Immunol. 2023 Sep 1;14:1240419. doi: 10.3389/fimmu.2023.
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This page was last updated on Tuesday, March 4, 2025