3.4 Interleukin-25 (IL-25)
IL-25 is a member of the interleukin-17 cytokine family that recognizes
a receptor composed of IL-17RB and IL-17RA subunits [58]. IL-17RB
receptor is mainly expressed on ILC2, and its activation is involved in
type 2 effector response [58-61]. In C57BL/6J mice, exposure to RSV
induced the expression of IL-25 and IL-17RB lung transcripts and of
other potentially pathogenic cytokines, including IL-13 [61].
Treatment with an anti-IL-25 antibody significantly reduced Th2 cytokine
production, mucus-associated gob5 gene expression and airway
hyperresponsiveness. Moreover, IL-17RB−/− mice showed
increased clearance of the virus and diminished pathology [61]. In a
different set of experiments, IL-17RB−/− mice were
sensitized to allergen, infected with RSV during the active allergic
responses, and then challenged with allergen [62]. As compared to
wild-type mice, decreased inflammatory response, cytokine production and
IL-13 and gob5 gene expression was detected in
IL-17RB−/− mice, possibly reflecting enhanced
clearance of RSV, leading to decreased immune activation [61].
Immune and morphological responses to RSV infection were also evaluated
in wild-type and NK cell-depleted BALB/c mice [62]. NK cells play a
critical role in the development of an effector immune response in RSV
infection [63]. Depletion of NK cells led to increased IL-25
expression in the respiratory epithelium, higher IL-4, IL-13 and eotaxin
lung mRNA levels and higher serum IgE, tissue eosinophil numbers and
mucus-secreting cells. This increased Th2 pathology was reflected in a
delayed viral clearance in the later stages of infection [61].
RSV-induced Th2 responses were IL-25 dependent. Treatment of NK-depleted
mice with anti-IL-25 antibodies led to attenuation of the Th2 cell
responses, suppression of inflammation and histopathological changes in
the lungs [62].
4. GUT MICROBIOTA, RSV INFECTION, ALARMINS AND ILC2
Gut microbiota composition might affect the severity of respiratory
virus infections, but the interaction can be bidirectional, since
infections can induce gut dysbiosis [64,65]. The high concentration
of microorganism- and pathogen-associated molecular patterns
physiologically present in the gut and the huge amounts of cytokines and
chemokines produced during dysbiosis can activate local ILC that can
then migrate to other sites of the body [19-21]. In an integrated
microbiota dysbiosis mice model, it was demonstrated that gut microbiota
can modulate ILC2 directional migration to the lung via regulation of
select cytokines [66]. In these mice, Proteobacteriaabundance was associated with increased IL-33 production which promoted
ILC2 migration and accumulation in the lung. Blocking the IL-33 receptor
with anti-ST2 antibodies, abolished the observed increased percentages
of lung ILC2 in this animal model
[65]. Moreover, tissue and
circulating ILC2 can recognize microbial ligands through their TLR,
and directly produce a variety of
cytokines, chemokines which can fight or promote infections [19-21,
67-70]. In stool samples collected from infants hospitalized during a
bronchiolitis season, four microbiota profiles were detected:Escherichia -dominant, Bifidobacterium -dominant,Enterobacter /Veillonella -dominant, andBacteroides -dominant [71]. The proportion of infants with
bronchiolitis (related to RSV infection in 65% of them) was lowest in
the Enterobacter /Veillonella -dominant profile and highest
in the Bacteroides -dominant profile [71]. To determine
whether a
specific gut microbial profile
could be associated with RSV severity, stool samples were collected in
95 infants during an RSV season: 37 were healthy babies and 58 were
hospitalized with RSV bronchiolitis [18]. Out of the RSV positive
infants, 53 remained in the pediatric ward and 5 later moved to the
pediatric intensive care unit. There was a significant enrichment inBacteroides , and a decrease in Firmicutes in RSV infants
vs. healthy controls. In addition, infants with severe RSV disease had
slightly lower alpha diversity
(richness and evenness of the
bacterial community) of the gut
microbiota compared to infants with moderate RSV and controls. Beta
diversity (overall microbial composition) was significantly different
between all RSV patients compared to controls [18]. These results
were confirmed in BALB/mice in which, after RSV infection, showed a
significant increase in the relative abundance
of Bacteroidetes and a corresponding decrease
in Firmicutes was detected (figure 3A) [72]. Interestingly,
many members of the Bacteroidetes phylum use mucus as an energy
source [73] and Muc5ac mucin levels were significantly increased in
the airways and colon of RSV-infected mice, but not in control mice.
Changes in gut microbiota composition following RSV infection
may
also indirectly regulate ILC2
function through the production of alarmins. 6-to-8-week-old BALB/c male
mice were randomly divided into a control (CON) group, an ovalbumin
(OVA) sensitized group, and an OVA + RSV group [73]. Compared with
the CON group, the OVA group had lower abundance of bothBacteroidetes and Firmicutes (figure 3B), whereas higher
abundance of these phyla was detected in the OVA + RSV group, compared
with the OVA group (figure 3C). RSV-infected asthmatic mice had
increased expression of IL-25 and IL-33 and of the Th2 cytokines IL-4,
IL-5, and IL-13 [74]. Prevotellaceae_NK4A136 _group, which
belongs to the Bacteroides species, was significantly associated
with IgE, IL-33, IL-25, IL-5, and IL-13 levels, whereasLachnospiraceae_NK4A136_ group which belongs to theFirmicutes species, was significantly associated with IgE and
IL-33 levels [74]. Aggravation of bronchial hyperresponsiveness to
methacholine and airway inflammation was observed in asthmatic mice
following RSV infection-induced alteration of gut microbiota.
Interestingly, in a study comparing children with recurrent respiratory
tract infections (RRTI) and a healthy control group, distinct gut
bacterial community structures between the groups were observed with an
enrichment in Bacteroidetes in the RRTI group [75]. Whether
probiotics and/or bacterial derived products, potentially involved in
immune training, could affect gut dysbiosis, prevent GIT epithelial
dysfunction and the related negative influence on the immune system is
an interesting hypothesis that needs to be adequately addressed and
demonstrated [76,77].