3.1 Modulation of RSV infection severity
In infants, RSV bronchiolitis severity is linked to a dysregulation of
the immune response, related to a relative immaturity of the host
defenses [3]. Recent literature suggests that
prior or concomitant colonization
of nasopharyngeal microbiota by potentially pathogenic bacteria may
enhance the severity of the RSV infection [7,22,23]. A 17-site,
multicenter, prospective cohort study of 1,016 infants (age <1
year) hospitalized with bronchiolitis, showed that during RSV infection
a greater abundance of Haemophilus influenzae andStreptococcus pneumoniae in the nasal microbiota can be
associated with more severe disease (figure 2A)
[22]. In a
prospective observational study,
during four consecutive seasons, 106 young children with a first episode
of RSV infection and 26 healthy control subjects were enrolled [7].
Three groups of children less than 2 years of age were evaluated: a)
with mild RSV disease (RSV infection), b) with severe RSV disease (RSV
hospitalization) and c) healthy controls. Five nasopharyngeal microbiota
clusters were identified, characterized by enrichment of eitherHaemophilus influenzae , Streptococcus ,Corynebacterium , Moraxella , and Staphylococcus
aureus [7]. RSV infection and
hospitalization were positively associated with Haemophilus
influenzae and Streptococcus and negatively associated withStaphylococcus aureusabundance (figure 2A).
Rates of PICU admission and length
of stay tended to be lower in children within the Moraxellacluster than in children included in the other clusters and higher
abundance of Moraxella was observed most often in outpatients
[7]. Independently from microbiota cluster, children with RSV
infection showed overexpression of IFN-related genes. However, in those
with transcriptome profiles dominated by Haemophilus influenzaeand Streptococcus , an upregulation of genes linked to toll-like
receptor and neutrophil-macrophage activation and signaling was also
detected. Overexpression of Haemophilus and loss in commensals,
like Veillonella , were described in nasopharyngeal aspirates of a
cohort of 54 infants, younger than 6 months of age, hospitalized with
RSV infection [24]. Transcriptome profiles dominated byHaemophilus was associated with increase IL-6 and CXCL-8
responses, cytokines that in respiratory virus infections are associated
with more severe disease (figure 2A). [24-26]. Moreover, in human
bronchial epithelial cell culture pretreated with Haemophilus
influenzae , the release of IL-6 and CXCL-8 was synergistically
increased after RSV, but not after HRV infection, buttressing the notion
that this virus-bacterial interplay is specific for RSV [27]. The
clinical implication of these observation is reflected in a multicenter
prospective cohort study of 1,005 infants hospitalized for
bronchiolitis. In this study the odds ratio for PICU admission was
higher for subjects with RSV infection and Haemophilus -dominant
profiles compared to RSV-infected infants with profiles dominated by
other bacteria, such as Moraxella(figure 2A) [28]. Thus,
specific nasopharyngeal microbiota clusters, dominated byHaemophilus influenzae and Streptococcus pneumoniae can
modulate the host immune response, potentially affecting clinical
disease severity. Further evidence for the ability of the nasopharyngeal
microbiota to positively modulate the host immune response is the
demonstration of the presence of specific metabolic profiles, linked to
the microbiome composition, in children with severe bronchiolitis. In a
multicenter prospective cohort study on infants <1 year of
age, hospitalized with bronchiolitis, Stewart et al. determined
microbiome profiles and metabolome in nasopharyngeal airway samples and
their association with disease severity [22]. Among 254 metabolites
identified, a panel of 25 showed high sensitivity (84%) and specificity
(86%) in predicting the use of positive pressure ventilation (PPV)
support. Metagenomic sequencing demonstrated that Haemophilus
influenzae , Moraxella catarrhalis , and Streptococcus
pneumoniae dominated the nasopharyngeal airway. Of these, however, only
the relative abundance of Streptococcus pneumoniaecorrelated with the intensity of these selected metabolites to predict
increased risk of PPV support (figure 2A). In the pathway analysis,
sphingolipid metabolism was the sub-pathway most significantly enriched
in infants with PPV use, and in turn, enrichment of sphingolipid
metabolites was positively correlated with the relative abundance ofStreptococcus pneumoniae [22]. In contrast, the
relative Moraxella abundance was negatively correlated with
respective intensity of the same metabolites. Sphingolipids are linked
to the inflammatory-mediated pathogenesis of airway diseases and play an
important role in multiple aspects of viral replication, including the
initial infection of mammalian cells, depression of host immune
response, and assembly and budding of newly synthesized viral components
[29]. Thus, curiously, Moraxella spp, thought to be
associated with a general increase in infant morbidity [11,13],
appears to have a “protective effect” on RSV bronchiolitis.