Biomarkers of viral infections in exacerbation of allergic rhinitis and asthma
Text box: Respiratory viral infections may exacerbate chronic airway inflammatory diseases, including allergic inflammation through both Type 2 (e.g., IL-25, IL-33 and TSLP) and non-type 2 (e.g., IFN types I and III, RIP3, OSM, MCIDAS) mechanisms.
Over the past decade, our understanding of immunological mechanisms underlying allergic diseases such as AR has substantially increased through the discovery of T helper (Th) subsets and their importance in allergic inflammation. Emerging data now provide new insights on the type 2 immune response that is an immune response to allergens and involves Th2 cells, type 2 B cells, ILC2s, type 2 macrophages, a small fraction of IL-4-secreting NK cells, IL-4-secreting NK-T cells, basophils, eosinophils and mast cells.101 At the same time, it has also been established that viral infection synergizes with allergic inflammation causing more severe exacerbations and symptoms compared to both conditions alone.102,103 There is increasing evidences that most respiratory viral infections could trigger or exacerbate chronic type 2 inflammatory responses via excessive release of chemokines and cytokines into the airways.104-106 While much of these studies focuses on lower airway inflammatory diseases instead of AR; insights from these studies can be applied to ongoing studies of viral induced AR exacerbations and the search for its associated markers.
Like other chronic airway inflammatory diseases, AR patients also suffer from altered responses and potentially increased susceptibility towards viral infection.107-109 This is similarly due to the reduced type III interferon response, which is crucial against incoming viral infection in the upper airway.107-109 Hence, markers for virus induced AR exacerbation may have significant overlap with findings from other inflammatory airway diseases. Proinflammatory cytokines such as TNF-α, IL-4, IL-5, IL-13, RANTES, Eotaxin, TSLP, IL-25 and IL-33 are usually expressed at higher concentrations in chronically inflamed airways, some of which are also found in AR.101,110,111 These cytokines can be further triggered directly or indirectly by viral induced IFNs, cytokines and chemokines. Infections such as RSV can even further shunt antiviral responses towards a more type 2 centric response.112-116 In addition, the discovery of ILC2s, a group of lymphoid cells, further emphasized the role of epithelial alarmins IL-25, IL-33 and TSLP in viral induced exacerbation.117 During viral infection, these three cytokines were secreted in response to epithelial injury.118-120 They then activate ILC2s to further secrete type 2 cytokines IL-4, IL-5 and IL-13, aggravating type 2 inflammation in the airway, resulting in acute viral exacerbation. Interestingly, these factors are not released readily and do not activate ILC2s in virus-infected healthy individuals, but effectively augment type 2 responses in chronically inflamed airways (Figure 4) .121,122
In addition, respiratory viral infections may also exacerbate chronic airway inflammatory diseases, including allergic inflammation through other non-type 2 mechanisms, in which other markers can also be used as an indicator of these exacerbations. Viral infections can lead to the destruction of epithelial barrier and disruption of mucociliary function due in part to cell death in the virus infected epithelium. Hence, markers for cell death (e.g. RIP3) and mucociliary dysfunction (e.g. MCIDAS) constitute part of the viral exacerbation repertoire.112 Viral infection also causes increase in factors such as OSM and ANGPTL4 which disrupts tight junctions leading to increased allergen invasion and their contact with immune cells in the sub-epithelium region, thereby exacerbating allergic symptoms.123,124 In addition, miRNAs are increasingly implicated in the mis-regulation of inflammatory responses and several of them are found to be dysregulated in an inflamed airway. For example, expressional changes of miRNAs such as miR-21 may coincide with viral infection responses and hence linked to viral induced exacerbations.125 Finally, an emerging field of bioenergetics and mitochondrial function may also contribute to the mechanism of viral induced exacerbation in AR. Oxidative stress and mitochondrial dysfunction from viral infection may induce increased inflammation and thus ROS and its associated markers may potentially serve as key markers for viral exacerbation.126,127