Insights Into Type I and III Interferons in Asthma and Exacerbations

Abstract

Asthma is a highly prevalent, chronic respiratory disease that impacts millions of people worldwide and causes thousands of deaths every year. Asthmatics display different phenotypes with distinct genetic components, environmental causes, and immunopathologic signatures, and are broadly characterized into type 2-high or type 2-low (non-type 2) endotypes by linking clinical characteristics, steroid responsiveness, and molecular pathways. Regardless of asthma severity and adequate disease management, patients may experience acute exacerbations of symptoms and a loss of disease control, often triggered by respiratory infections. The interferon (IFN) family represents a group of cytokines that play a central role in the protection against and exacerbation of various infections and pathologies, including asthma. Type I and III IFNs in particular play an indispensable role in the host immune system to fight off pathogens, which seems to be altered in both pediatric and adult asthmatics. Impaired IFN production leaves asthmatics susceptible to infection and with uncontrolled type 2 immunity, promotes airway hyperresponsiveness (AHR), and inflammation which can lead to asthma exacerbations. However, IFN deficiency is not observed in all asthmatics, and alterations in IFN expression may be independent of type 2 immunity. In this review, we discuss the link between type I and III IFNs and asthma both in general and in specific contexts, including during viral infection, co-infection, and bacterial/fungal infection. We also highlight several studies which examine the potential role for type I and III IFNs as asthma-related therapies.

Keywords: asthma; asthma therapeutics; infection; interferon-alpha; interferon-beta; interferon-lambda; type I interferon; type III interferon.

FIGURE 1

Viral induction and evasion of type I and III interferon response. Infection with RSV, RV, hPIV, hMPV, or IAV causes production of type I and III IFNs (left) through PRR signaling including TLRs and RLRs. These viruses have evolved functions to evade the IFN response (right) either by preventing PRR recognition or blocking the activity of downstream factors like IRF3 or STAT1. Figure created in BioRender.com.

FIGURE 2

Type I and III interferon induction and T helper cell response to respiratory pathogens in the asthmatic lung. Type I and III IFNs are known to have overlapping innate and adaptive roles in the lung and decreased IFN response to respiratory infection in asthmatics is thought to contribute to acute exacerbations. Cross-inhibition between type 2 responses and type I and III IFNs have been reported in the context of type 2-high asthma and acute viral exacerbations. Type I and III IFNs also can alter Th1 and Th17 responses and may directly and indirectly influence type-2 low asthma and exacerbations of disease. Further, pathogens can influence T helper cell responses independent of IFN as well, directly altering the inflammatory environment in the asthmatic lung. Figure created in BioRender.com.