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].