Viral Induced Effects on a Vulnerable Epithelium; Lessons Learned From Paediatric Asthma and Eosinophilic Oesophagitis

Abstract

The epithelium is integral to the protection of many different biological systems and for the maintenance of biochemical homeostasis. Emerging evidence suggests that particular children have epithelial vulnerabilities leading to dysregulated barrier function and integrity, that resultantly contributes to disease pathogenesis. These epithelial vulnerabilities likely develop in utero or in early life due to various genetic, epigenetic and environmental factors. Although various epithelia are uniquely structured with specific function, prevalent allergic-type epithelial diseases in children potentially have common or parallel disease processes. These include inflammation and immune response dysregulation stemming from atypical epithelial barrier function and integrity. Two diseases where aetiology and pathogenesis are potentially linked to epithelial vulnerabilities include Paediatric Asthma and Eosinophilic Oesophagitis (EoE). For example, rhinovirus C (RV-C) is a known risk factor for paediatric asthma development and is known to disrupt respiratory epithelial barrier function causing acute inflammation. In addition, EoE, a prevalent atopic condition of the oesophageal epithelium, is characterised by similar innate immune and epithelial responses to viral injury. This review examines the current literature and identifies the gaps in the field defining viral-induced effects on a vulnerable respiratory epithelium and resulting chronic inflammation, drawing from knowledge generated in acute wheezing illness, paediatric asthma and EoE. Besides highlighting the importance of epithelial structure and barrier function in allergic disease pathogenesis regardless of specific epithelial sub-types, this review focuses on the importance of examining other parallel allergic-type disease processes that may uncover commonalities driving disease pathogenesis. This in turn may be beneficial in the development of common therapeutics for current clinical management and disease prevention in the future.

Gene‐environment interactions in childhood asthma revisited; expanding the interaction concept

“…40 RV is detected in most children who receive medical care for asthma exacerbations and is known to exacerbate preexisting asthma. 40 Impaired epithelial barrier and functionality, as well as dysregulated immune responses, have been suggested as perpetuating mechanisms, perhaps even more so in children with a predisposition for epithelial dysfunction and future asthma. 40,44 In fact, children with RV infections show impaired epithelial wound repair, which is magnified in asthmatic airways.…”

“…40 Several mechanisms are involved, including mucociliary function, structural protection, and coordination of immunological responses. 40 Airway epithelial dysfunction and remodeling have a significant role in asthma pathogenesis and have been linked to disease onset and progression. 41 Several asthma susceptibility genes are expressed in airway epithelial cells and/or have a direct role in epithelial functionality.…”

“…[40][41][42] The effect of the exposure to certain environmental factors early in life on the modification of the risk and severity of asthma later in childhood 40,41 is partially dependent on the functionality and integrity of the airway epithelium. 40,43 Indeed, environmental exposures can trigger an inflammatory response and the disruption of the barrier and mucociliary function, as well as the maintenance of respiratory homeostasis. 40,41 Children with a predisposed dysfunctional epithelium are particularly vulnerable to these adverse effects.…”

“…40,43 Indeed, environmental exposures can trigger an inflammatory response and the disruption of the barrier and mucociliary function, as well as the maintenance of respiratory homeostasis. 40,41 Children with a predisposed dysfunctional epithelium are particularly vulnerable to these adverse effects. 40 Respiratory infections are common insults in young children, particularly rhinovirus (RV) infections, which have been linked…”

“…40 Impaired epithelial barrier and functionality, as well as dysregulated immune responses, have been suggested as perpetuating mechanisms, perhaps even more so in children with a predisposition for epithelial dysfunction and future asthma. 40,44 In fact, children with RV infections show impaired epithelial wound repair, which is magnified in asthmatic airways. ORMDL3, and IKZF3, together with flanking genes such as PGAP3, ERBB2, and GSDMA.…”