Introduction
Respiratory viruses such as rhinoviruses, the main cause of the common cold, are among the most frequent triggers of asthma attacks and other inflammatory airway conditions. Although these infections are usually mild in healthy individuals, they can cause severe breathing problems, prolonged inflammation, and worsening lung function in susceptible people. The cells lining the airways, known as airway epithelial cells, form the body’s first line of defense against inhaled viruses. These cells actively detect viruses and coordinate immune responses that help eliminate infection while limiting tissue damage.
One of the most important antiviral defense mechanisms in airway epithelial cells involves the production of molecules called interferons. Interferons act as warning signals that help neighboring cells prepare for viral attack and activate antiviral immune defenses throughout the body. However, during rhinovirus infection, the same airway cells can also activate inflammatory pathways that contribute to mucus production, tissue irritation, and airway narrowing. In diseases such as asthma, this inflammatory response can become harmful. Understanding why airway epithelial cells sometimes mount protective antiviral responses and other times shift toward damaging inflammation remains a major unanswered question in respiratory medicine.
In this study, we investigated whether the metabolism of airway epithelial cells, including not only how cells generate energy but also how metabolic molecules directly regulate immune function, influences how these responses are controlled during rhinovirus infection. Researchers increasingly recognize that metabolism and immunity are closely interconnected, as metabolic intermediates can act as signaling molecules that shape antiviral defenses and inflammation. However, little was known about how virus-induced metabolic changes in airway epithelial cells influence the balance between protective antiviral responses and harmful inflammation during respiratory infections.
We focused on a key antiviral sensor called RIG-I, a protein that detects viral genetic material inside infected cells. Once activated, RIG-I can trigger two very different immune pathways. In one pathway, RIG-I promotes the production of interferons that help fight the virus. In the other, it becomes part of inflammatory protein complexes called inflammasomes, which drive the release of inflammatory molecules such as IL-1β. While inflammation is important for fighting infections, excessive inflammasome activation can damage tissues and worsen lung disease. We wanted to understand how cellular metabolism influences the balance between these protective and harmful RIG-I responses.
Materials and methods
To address this question, we infected primary human airway epithelial cells with different types of rhinovirus and analyzed them using metabolomics, proteomics, and single-cell RNA sequencing. We also used gene-editing approaches and metabolic inhibitors to selectively block different pathways involved in energy production. This enabled us to determine how specific metabolic processes influence antiviral signaling and inflammatory responses.
Results
Our results showed that rhinovirus infection profoundly alters the metabolism of airway epithelial cells. Infected cells displayed mitochondrial dysfunction together with increased reliance on glycolysis, a rapid but less efficient way of generating energy. Importantly, different metabolic pathways had opposite effects on immune responses. Blocking mitochondrial energy production weakened antiviral interferon responses while increasing inflammatory activation of the RIG-I inflammasome. In contrast, inhibiting glycolysis reduced viral replication and dampened inflammatory signaling. These findings demonstrate that metabolism acts as a central regulator of how airway cells respond to viral infection. Single-cell analyses further revealed that rhinovirus infection alone can push healthy airway epithelial cells into metabolic and inflammatory states resembling those observed in asthma.
Discussion
Overall, our study identifies cellular metabolism as a critical factor controlling the balance between antiviral protection and harmful inflammation during rhinovirus infection and highlights potential therapeutic targets for reducing virus-induced airway inflammation and asthma exacerbations.