When Ellen Foxman began her postdoctoral work at Yale School of Medicine (YSM) in 2010, she was interested in what respiratory viruses could reveal about the human immune system. Having a young son diagnosed with asthma around the same time only sharpened this interest.
“The number one trigger of asthma attacks is rhinovirus,” said Foxman, now an associate professor of laboratory medicine and immunobiology at YSM who leads a research program studying how the immune system interacts with viruses that cause respiratory diseases. “In the past, people believed asthma attacks were due to allergies, but better virus detection technology showed us years ago that rhinovirus is a major cause.”
Still, a vexing question remained: Why does the same virus cause only mild sniffles in some people but lead to severe breathing problems in others, particularly people with conditions like asthma or chronic obstructive pulmonary disease (COPD)?
In her latest research, Foxman showed that the answer lies in the body’s response to the virus, not in the inherent power of the virus.
Specifically, she found that the reaction of the cells that form the lining of the nasal passages plays a larger role than was previously understood. These cells have an arsenal of innate defense mechanisms triggered by viruses (also called “innate immunity”), even though they are not part of the traditional immune system. Foxman’s lab identified a switch that determines whether a rhinovirus infection remains a mild cold or escalates into the kind of severe airway inflammation that can land someone in the emergency room.
The findings are published in the journal Cell Press Blue.
“What’s clear is that it’s not just the virus that determines the disease. There’s something about the human body that’s really driving the disease outcome, but the mechanisms are not well understood,” said Foxman, senior author of the study. “We set out to understand the mechanisms inside virus-infected cells that push the infection in one direction or another.”
Foxman and colleagues in the lab.
All in the nose
The body’s first-line antiviral defense in the nose — called the interferon response — usually keeps rhinovirus under control. When the response works properly, fewer than 2% of nasal cells become infected with rhinovirus, and the cold peters out.
For the new study, researchers used a laboratory model that closely mimics the human nasal lining and grew real human nasal cells into organoids that were able to develop cilia and produce mucus, replicating the inside of the nose and lungs. Next, they infected the cells with rhinovirus and used drugs to selectively block different immune signaling pathways, so that they could see what would happen if the interferon response or other defenses are blocked.
Electron micrograph of differentiated human nasal epithelial organoids with cilia of multiciliated cells accentuated in blue.
They then used single-cell RNA sequencing, which allowed them to see how individual cells responded to infection. Specifically, it revealed which cells were infected, which defensive genes were turned on, and how nearby uninfected cells reacted. The researchers also measured virus levels, cell death, mucus production, and pinpointed the role of inflammatory sensors.
They found that most cold virus infections stay mild because the nasal lining rapidly produces interferons that stop the virus from spreading to other cells. But when that response is weakened or blocked, the body reacts with a more aggressive inflammatory mode that can worsen symptoms and damage airways. Strong, speedy interferon signaling limits infection and keeps the virus and inflammation in check, while weak interferon responses or other factors that promote an aggressive response allow runaway inflammation.
“Our experiments with organoids show that a rapid interferon response by the infected cells is extremely effective for shutting down rhinovirus, even without any cells of the immune system present,” said first author Bao Wang, a Ph.D. student in Yale’s Department of Immunology and a member of Foxman’s lab.
Zeroing in on inflammation
Targeting different responses using drugs and genetic changes in organoids helped researchers get a better idea of how the body activates inflammatory signals. These insights may help researchers create or repurpose medications that could reduce dangerous airway inflammation, which could in turn help prevent rhinovirus-induced asthma and COPD attacks.
“One very unique aspect of this study was being able to look at thousands of cells working together and how they interact to fight this common infection,” Foxman said.
The underlying question, of course, is what would make a person’s interferon response weak in the first place? Why doesn’t everyone’s response simply knock out rhinovirus before it gets a hold?
“That’s a great question,” Foxman said. “In our model, we inhibited the response with a drug, but it’s known that in people with chronic airway diseases, the interferon response is lower than in a healthy person. That’s the ‘why’ we just don’t know yet. It’s our next step.”
Other study contributors included postdoctoral fellow Julien Amat and research associate Valia Mihaylova in the Foxman Lab at Yale School of Medicine; research scientist Guilin Wang in the Yale Department of Molecular Biophysics and Biochemistry; and senior research scientist Yong Kong in the Department of Biostatistics at the Yale School of Public Health.
