1. INTRODUCTION
Respiratory syncytial virus (RSV) is a common and highly contagious pathogen inducing acute respiratory tract infections in infants [1]. Although in many cases symptoms remain mild, a subset of individuals develops severe RSV-associated bronchiolitis [1,2]. The severity of the disease in infancy, thought to be related to the physiological immaturity of the immune system, is also linked to an increased risk of recurrent wheezing in later life [3,4]. This phenomenon is not always associated to atopic sensitization but is thought to be related to long-term immune response alterations and neuromuscular tone instability in the airways [3,4]. The airway epithelium, the primary target of RSV infection, is an important component of the antiviral response, acting both as a physical fence and as an immunological barrier able to elicit inflammatory and immune mediate responses [5]. Recognition of RSV transcripts and viral replication intermediates by bronchial epithelial cells (BECs) induces the production of type I and type III IFNs and other cytokines, all geared to mount an effective antiviral reaction [3,5]. However, BECs may also be programmed to release mediators that activate a Th2 immune response, aggravating the infection, and contributing to airway damage [6]. These mediators include thymic stromal lymphopoietin (TSLP), IL-33, the high mobility group box 1 (HMGB1) and IL-25 [6,7]. Often characterized as “alarmins”, these epithelial cell-derived proteins regulate a broad spectrum of immune cell populations and are particularly potent in eliciting and activating type 2 innate lymphoid cells (ILC2) in a variety of lung disorders, including RSV bronchiolitis and recurrent wheezing/asthma in childhood [7-12]. It is therefore possible that, following a first severe respiratory infection in early life, long-term epithelial cell progenitors or persistent epigenetic modifications leading to alarmin-induced ILC2 activation may be involved in the ongoing increased susceptibility to obstructive lung diseases [13]. Through DNA methylation and histone ubiquitination, RSV can induce epigenetic modifications in BECs that favor Th2 responses [14], promoting post bronchiolitis wheezing [15]. In RSV-infected BEC cultures, upregulation of the expression of the epigenetic regulator histone deacetylase2 (HDAC2) was associated with increased viral replication and production of pro-inflammatory cytokine, and oxidative stress-related molecules [16]. Evaluating cells obtained by nasal brushing at age 6 in preterm infants, who received RSV immunoprophylaxis with palivizumab or placebo during their first RSV season, demonstrated that palivizumab had global and persistent effects on nasal DNA methylation patterns, relevant innate immune viral response, and viral budding genes [17]. These data suggest that RSV-induced epigenetic modification in airway cell functions could represent a common pathogenetic imprint in severe RSV bronchiolitis and subsequent recurrent wheezing/asthma in childhood. Finally, ILC2 activation and disease severity can also be regulated through the production of alarmins by RSV-induced gut microbiome dysbiosis, as shown in infants with bronchiolitis [18].