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