Why some people get bad colds and others don’t

"As the number one cause of common colds and a major cause of breathing problems in people with asthma and other chronic lung conditions, rhinoviruses are very important in human health," says senior author Ellen Foxman of Yale School of Medicine. "This research allowed us to peer into the human nasal lining and see what is happening during rhinovirus infections at both the cellular and molecular levels."

Creating Lab Grown Human Nasal Tissue

To closely observe how nasal cells respond to infection, the research team built a lab grown model of human nasal tissue. They grew nasal stem cells for four weeks while exposing the upper surface of the tissue to air. This setup encouraged the cells to mature into a structure that closely resembles the lining of the nasal passages and lung airways.

The resulting tissue contained multiple cell types found in the human airway, including mucus producing cells and cells with cilia. Cilia are tiny hair like structures that help move mucus and trapped particles out of the lungs.

"This model reflects the responses of the human body much more accurately than the conventional cell lines used for virology research," Foxman says. "Since rhinovirus causes illness in humans but not other animals, organotypic models of human tissues are particularly valuable for studying this virus."

Interferons and Early Antiviral Protection

Using this model, the researchers were able to monitor how thousands of individual cells respond together during infection. They also examined what happened when the cellular sensors responsible for detecting rhinovirus were blocked. These experiments revealed a powerful defense system coordinated by interferons, which are proteins that interfere with viral entry and replication.

When nasal cells detect rhinovirus, they release interferons that activate antiviral defenses not only in infected cells but also in nearby healthy cells. This coordinated response makes it difficult for the virus to reproduce and spread. If interferon activity begins quickly, the infection can be contained early. When the researchers blocked this response, the virus spread rapidly, infecting many more cells and causing significant damage. In some cases, the infected organoids did not survive.

"Our experiments show how critical and effective a rapid interferon response is in controlling rhinovirus infection, even without any cells of the immune system present," says first author Bao Wang of Yale School of Medicine.

When Viral Growth Triggers Harmful Responses

The study also uncovered additional responses that occur when viral replication increases. Under these conditions, rhinovirus can activate a separate sensing system that leads both infected and uninfected cells to produce large amounts of mucus and inflammatory signals. This reaction can contribute to airway inflammation and breathing difficulties in the lungs.

According to the researchers, these pathways may offer useful targets for treatments aimed at reducing harmful symptoms while supporting effective antiviral defenses.

Limits of the Model and Future Research

The team notes that their organoid model includes fewer cell types than are present in the human body. During real infections, additional cells, including immune cells, are drawn to the site to help fight the virus. The researchers say that understanding how these additional cell types and environmental factors in the nasal passages and airways influence the body's response to rhinovirus will be an important focus of future work.

"Our study advances the paradigm that the body's responses to a virus, rather than the properties inherent to the virus itself, are hugely important in determining whether or not a virus will cause illness and how severe the illness will be," Foxman says. "Targeting defense mechanisms is an exciting avenue for novel therapeutics."