Unmasking programmed cell death in rhinovirus-driven asthma pathology

Abstract Rhinovirus (RV) infection is responsible for the majority of cases of viral exacerbations of asthma. Understanding the cellular and molecular mechanisms that cause asthma exacerbations is an absolute requirement for the development of effective treatments. Emerging literature suggests that cell death may have an important role in RV-induced exacerbations. Several types of programmed cell death (PCD) have been implicated in asthma, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Increased presence of apoptotic airway epithelial cells in the sputum of adult and paediatric asthma patients is suggestive of defects in apoptosis. Elevated levels of phosphorylated mixed lineage kinase domain-like protein and receptor-interacting serine/threonine-protein kinase 3, markers of active necroptosis, have been found in the serum of asthmatic patients. Gasdermin B, a member of the gasdermin family of pyroptosis executioner proteins, has a strong genetic linkage to severe asthma. Expression level of GSDMB correlated with asthma exacerbations and antiviral pathways. Lipid peroxidation and increased airway iron levels, both suggestive of ferroptosis, have been observed in asthma patients. RV infection of epithelial cells triggers an inflammatory response, which can provide the necessary pro-inflammatory chemokines and cytokines to initiate PCD, such as tumour necrosis factor-α. RV exploits PCD such as apoptosis, necroptosis, pyroptosis, and ferroptosis to aid its replication and release, while modulating them probably to limit immune response. In the present review, we investigate the concept that pro-inflammatory PCD pathways modulated by RV infection in the context of asthma lead to prolonged inflammatory and immune responses that are key to asthma exacerbations.