‘Nose in a Dish’ reveals why colds are worse for some people than others

A new lab has used a ‘nose in a dish’ to understand why colds cause mild symptoms in some people and send others to the hospital.

When cold and flu season is in full swing, rhinoviruses, the most common cause of colds, can make many of us miserable, causing symptoms such as runny noses, sore throats, and mild coughs. However, for some people, rhinovirus infection is a more serious condition.

For example, in smokers and people with asthma, rhinoviruses can cause life-threatening breathing difficulties and require treatment. Variants of the same rhinovirus can cause vastly different medical outcomes depending on who it infects.

you may like

Now, a new study published January 19 in the journal Cell Press Blue has demonstrated that this variation relies on the activation of different immune programs within infected nasal tissue. The research team grew miniature models of human nasal passages in dishes to study how cells respond to infection.

They say the discovery is a step toward developing effective antiviral drugs for the common cold.

How to grow a nose in a plate

The cells that bear the brunt of cold infections are the epithelial cells that line the inside of your nose. When these cells detect a viral infection, they send a signal to the innate immune system, the body’s first non-specific line of defense against bacteria. Some of the first defenders this system deploys are molecules called interferons.

Despite knowing that interferons play an important role in fighting viruses, researchers have found it difficult to understand exactly how interferons play their role at the cellular level.

The new study, led by Dr. Ellen Foxman, an associate professor of experimental medicine and immunobiology at Yale University, used a technique called single-cell RNA sequencing to reveal what information is being sent from the cells’ control centers that house DNA. They performed their analysis at the resolution of individual nasal epithelial cells.

Foxman’s team cultured these cells in a dish environment that closely resembles the inside of a human nose. They then infected the cells with rhinovirus.

Claire Lloyd, a respiratory immunologist at Imperial College London who was not involved in the study, said this suite of techniques allowed Foxman’s team to gain new insights into how rhinoviruses affect nasal cells.

you may like

“I think it’s a combination of having multicellular organoids.” [the nose-in-a-dish]”Not only do we have more sensitive and specialized techniques to be able to see how ciliated cells are affected, how mucus-producing cells are affected,” Lloyd told Live Science. Both ciliated cells (cells with small hair-like projections) and mucus-producing cells are found in the lining of the nose.

Foxman’s first observation was that nasal cells are highly adept at fighting rhinoviruses, even when isolated from other parts of the body.

“During an optimal response, the virus infects only about 1% of cells, and the infection begins to resolve within a few days,” Foxman said in a statement. But when the researchers exposed the cells to drugs that inhibit interferon signaling, the cells’ previously strong defenses began to crumble.

In the latter condition, more than 30% of the cells were infected and the immune response was more pronounced. Levels of pro-inflammatory molecules, including cytokines, rose sharply, and mucus protein production increased significantly.

In the absence of interferon, one protein, nuclear factor kappa B (NF-κB), appears to be the primary conductor of this overreaction. This erratic reaction was similar to the reaction that often causes complications of severe rhinovirus infections in vulnerable patients.

Lloyd said if a person succumbs to a rhinovirus infection, it could indicate a problem with interferon production. “Some people have genetic defects in interferon production, which can affect the tone of the interferon response they produce,” she said.

Such laboratory studies are an important step toward treating common viral infections, but Lloyd cautioned that antiviral drugs that target the immune response must be carefully balanced.

“The immune system is very delicate,” Lloyd says. “If you just completely block NF-κB, you’re blocking all kinds of cytokines and chemokines, and you’re blocking the entire inflammatory response.” Inflammation can be harmful when it flares up out of control, but it’s necessary to effectively fight infection.

Foxman’s group tested several antiviral drugs in cell models, including an experimental drug called lupintrivir. The drug was particularly effective at suppressing excessive immune responses, at least in laboratory models. Lupintrivir previously failed to suppress rhinovirus infections in clinical trials in patients. But the study authors nevertheless suggested that the drug could have a second life as a treatment to reduce excessive immune responses to the virus in vulnerable populations such as patients with chronic obstructive pulmonary disease (COPD).

Mehul Sutar, a professor at the Emory Vaccine Center who was not involved in the study, said drugs that target the virus itself would be more accurate than those that target regulators of the immune response. For example, Lupintrivir targets viral proteins.

Rhinoviruses continue to be a persistent pest to humanity because they evolve rapidly in response to treatments, which can lead to the development of resistance to rhinoviruses. Only by understanding exactly why we get sick with colds can we find a solution.

“It’s obviously very difficult,” Stahl said. “Otherwise, there would be drugs for every virus.”