Shifting of Immune Responsiveness to House Dust Mite by Influenza A Infection: Genomic Insights

Abstract

Respiratory viral infections have been associated with an increased incidence of allergic asthma. However, the mechanisms by which respiratory infections facilitate allergic airway disease are incompletely understood. We previously showed that exposure to a low dose of house dust mite (HDM) resulted in enhanced HDM-mediated allergic airway inflammation, and, importantly, marked airway hyperreactivity only when allergen exposure occurred during an acute influenza A infection. In this study, we evaluated the impact of concurrent influenza infection and allergen exposure at the genomic level, using whole-genome microarray. Our data showed that, in contrast to exposure to a low dose of HDM, influenza A infection led to a dramatic increase in gene expression, particularly of TLRs, C-type lectin receptors, several complement components, as well as FcεR1. Additionally, we observed increased expression of a number of genes encoding chemokines and cytokines associated with the recruitment of proinflammatory cells. Moreover, HDM exposure in the context of an influenza A infection resulted in the induction of unique genes, including calgranulin A (S100a8), an endogenous damage-associated molecular pattern and TLR4 agonist. In addition, we observed significantly increased expression of serum amyloid A (Saa3) and serine protease inhibitor 3n (Serpina3n). This study showed that influenza infection markedly increased the expression of multiple gene classes capable of sensing allergens and amplifying the ensuing immune-inflammatory response. We propose that influenza A infection primes the lung environment in such a way as to lower the threshold of allergen responsiveness, thus facilitating the emergence of a clinically significant allergic phenotype.

Early life environmental predictors of asthma age‐of‐onset

“…Support for this finding can be found in recent studies reporting that children at the highest risk of developing asthma are those who, before 2 years of age, suffered from viral respiratory infections and allergic sensitization . It has also been postulated, based on results from a mouse model, that viral respiratory infections prime immunological pathways and lead to an increased responsiveness to house dust mite allergens, subsequent allergic sensitization and asthma . On the other hand, there is evidence for a causal relationship between allergic sensitization and an increased susceptibility to viral infections leading to asthma .…”

The mechanism or mechanisms driving atopic asthma initiation: The infant respiratory microbiome moves to center stage

“…54 Two related pathways have been described that might account for these observations. First, as initially reported in mouse models, [55][56][57] influenza and parainfluenza infections lead to upregulation of expression of the myeloid version of the high-affinity IgE receptor (FcεRI) on lung DCs; the precise mechanism or mechanisms involved remain to be elucidated but can include signals from a subset of incoming neutrophils recruited to the infection site. 56 It was suggested that cross-linking of this receptor with IgE directed against viral antigens might trigger local T H 2 cytokine production by virus-specific T H 2 memory cells, 57 but the existence of the latter remains unproved.…”

“…Alternatively, it has been shown that upregulation of this receptor in the parainfluenza model in animals presensitized to house dust mite allergen was associated with development of hyperresponsiveness to local allergen challenge, resulting in enhanced local production of T H 2 cytokines and reduced lung function. 55 The operation of a comparable pathway in human subjects is suggested by airway biopsy data demonstrating the presence of FcεRI 1 DCs in the bronchial mucosa of asthmatic patients 58 and in particular that this expression increases during periods of active disease. 59 Recent studies on acute severe asthma exacerbations in children resulting in hospitalization have shed some light on the underlying pathways involved.…”

The role of early life viral bronchiolitis in the inception of asthma

“…It was shown that murine parainfluenza LRTI causes an up-regulation of the high-affinity IgE receptor on lung antigen presenting cells, production of Th2 inflammatory cell and inflammatory mediators, and eventually results with an increased immune response to inhalant allergens 20–24 . The importance of the viral infection as the initial event (“the first hit”) to create airway allergic inflammation was further demonstrated in additional models involving innate immunity and invariant natural killer T cells 25, 26 .…”