Abstract
The immunopathology of respiratory syncytial virus (RSV) infection, the
most common cause of lower respiratory tract infections (LRTI) in the
pediatric population, with severe disease being the exception. The
variability of the clinical presentation is incompletely explained by
host, viral and environmental factors but, in infants and young
children, disease severity is certainly linked to the physiological
immune immaturity. There is evidence that the maturation of the host
immune response is, at least in part, promoted by the composition of the
nasopharyngeal microbiome that, modulating excessive inflammation, can
counteract the predisposition to develop viral respiratory infections
and lower the risk of disease severity. However, interaction between the
nasopharyngeal microbiota and respiratory viruses can be bidirectional.
Microbial dysbiosis can drive disease pathogenesis but may also
represents a reflection of the disease-induced alterations of the local
milieu. Moreover, viruses like RSV, can also increase the virulence of
potential pathogens in nasopharynx, which is a main reservoir of
bacteria, and therefore promote their spread to the lower airways
causing superinfection. Negative changes in microbial community
composition in early life may constitute a heightened risk towards
severe RSV respiratory infection and bacterial superinfection, whilst
specific groups of microorganisms can be associated with protection. A
better understanding into the potential negative and positive role of
the different nasopharyngeal bacterial species in disease prevention as
well as into the possible benefits of microbiome therapeutic
manipulation, may improve patient outcomes.
INTRODUCTION
Respiratory syncytial virus (RSV) is the main cause of acute viral
respiratory infection leading to hospitalization in infants and young
children worldwide [1]. The spectrum of its clinical manifestations
ranges from mild upper tract illness to severe LRTI. The latter,
requiring hospitalization in approximately 20% of the cases and of
these ~15% require intensive care management [2].
RSV virulence and a variety of environmental factors contribute to
increased RSV susceptibility, as well, specific host related conditions
have been identified which increase the risk for severe disease
[1-3], yet these are not present in most infants hospitalized with
RSV LRTI. The mechanisms accounting for the wide variability in the
clinical presentation of RSV infection are only partly understood, but
recent insights suggest that modifications of the nasopharyngeal
microbiota composition established or induced by a previous infection
might be involved. In early life, the baseline system structure and
function of the airway immunity is regulated by the local microbial
milieu, and distinct microbiota have been associated with sequelae of
specific viral and bacterial LRTI [4-6]. Recent insights suggest
that modifications of the nasopharyngeal microbiota composition,
established by a preceding infection, might be involved.
Whether imbalance in the microbial
community can drive disease pathogenesis or, conversely, reflects
disease-induced alterations of the local milieu following respiratory
infections is still to be elucidated [5,6]. A paradigmatic example
is represented by the bidirectional interplay between resident
nasopharyngeal bacterial communities and RSV in bronchiolitis.
Modifications of the upper airway microbiota composition appears to be
associated with RSV disease severity, at the same time there is evidence
that RSV can increase
the virulence of potential
nasopharyngeal pathogens, a large bacterial reservoir, that can
consequently spreads to the lower airways causing superinfection
[7,8]. The current evidences on the epidemiologic link between RSV
and nasopharyngeal microbiome, the mechanisms involved in these
interactions, and the possible clinical consequences will be reviewed,
summarized and discussed.
INFANT NASOPHARYNGEAL
MICROBIOME IN HEALTH AND DISEASE
The airways represent a large surface area that interacts with the
surrounding environment. They exhibit a gradient of bacterial load that
is relatively high in the nasopharynx and substantially diminished in
the lower respiratory tract [1]. A growing body of literature has
demonstrated that the nasopharyngeal microbiome, with its mixed
microbial communities, plays an important role in maturation and
homeostasis of the host immune response in the upper and lower airways
[1,4,5]. The balanced competitive/synergistic interplay between
commensal and potentially pathogenic taxa, that is the hallmark of a
healthy status, can be altered by acquisition of new pathogenic
bacteria, increased virulence or prevalence of potential pathogens,
and/or decreased efficiency of host defenses, the latter being the cause
but also the result of dysbiosis [1,4,6]. In newborns and infants,
obligatory nasal breathers, nasopharyngeal airways are both the first
line of defense but also the main port of entry for bacteria and
viruses. Overgrowth of virulent taxa will lead to symptomatic infection,
with surrounding tissue invasion and inflammation. [9]. Therefore,
in early life, microbiota composition of nasopharyngeal airways reflects
exposures to the surrounding atmospheric environment which, shaping the
host immune responses, will favor or inhibit the predisposition to
respiratory disorders [1,4,10-12]. Nasopharyngeal colonization by
environmental potential respiratory pathogens is established early in
childhood [2]. In a study on 234 infants, it was shown
that nasopharyngeal
microbiome has a relatively simple
structure, dominated by six clusters: Moraxella ,Haemophilus (Gram negative bacteria), Staphylococcus ,Corynebacterium , Streptococcus and Alloiococcus(Gram positive bacteria) (figure 1) [13]. Healthy nasopharyngeal
samples collected around 2 months of age were dominated byStaphylococcus and Corynebacterium, but the frequency of
these microbiome profile groups declined with age and, at 12 months of
age, an increased prevalence of Alloiococcus and Moraxellaspecies (spp) was detected (figure 1A) [13].
Transient incursions ofStreptococcus , Moraxella and/or Haemophilusoccurred during acute viral respiratory tract infections,Streptococcus and Moraxella colonizing, respectively, 54%
and 72% of the children by 1 year of age [14] and a progressive
decline in Staphylococcus andCorynebacterium spp (figure
1B) [13].
Antibiotic
treatments were associated with
higher abundances of the potential
respiratory pathogens Haemophilus , Streptococcus andMoraxella , with lower abundances of Alloiococcus andCorynebacterium (figure 1C) [13]. This microbial dysbiosis
may predict subsequent respiratory infections [2,15-17].
Colonization with Streptococcus , Moraxella orHaemophilus spp was linked to an increased risk for LRTI, whilst
nasopharyngeal microbiota dominated by Corynebacterium orAlloiococcus clusters was associated with less respiratory
morbidity (figure 1D)
[11-13].
When related to early exposure to
noxious environmental factors
negative changes in microbial community composition may constitute a
heightened risk towards severe viral respiratory infections and
bacterial superinfections [11,17]. This can be
observed in severely premature
infants admitted to neonatal intensive care units (NICU). These infants
face the combined effects of deprivation of the normal intrauterine
physical environment, supplemental oxygen with relative hyperoxia,
barotrauma from mechanical respiratory support, exposure to nosocomial
pathogens, and broad-spectrum antimicrobials [16]. They show
abnormal nasal airway immune responses against respiratory viruses,
persisting beyond the PICU period and, in comparison with full term
infants, a higher nasopharyngeal microbial heterogeneity and
within-group dissimilarity [18]. Emergence of a mixed flora,
including Moraxella and other Gram-negative bacteria
(Burkholderia , Neisseria and Janthinobacterium ),
was detected. At phylum level, an increase in Proteobacteria (a
major group of Gram-negative bacteria) was associated with a decrease inFirmicute (Gram-positive bacteria such as Lactobacillus )
(figure 1E) [14]. This airway microbiome signature has been recently
described also in preterm newborns at increased risk of bronchopulmonary
dysplasia [16,19]. The presence of within-group dissimilarity,
identified also in the nasopharyngeal microbiota of otherwise healthy
premature infants, suggests that this group does not develop a stable
microbiome in early life. Longitudinal data showed that these
prematurity-related microbiota features persisted during viral infection
and played important negative role in modulating airway inflammatory and
immune responses in this vulnerable group [16,19]. Upper airways
colonization by potential pathogens in neonates, also in term infants,
may be associated with increased susceptibility to LRTI during the first
3 years of life. A prospective birth cohort study of 411 children born
to mothers with asthma, showed that neonatal hypopharyngeal colonization
with Streptococcus pneumoniae , Haemophilus influenzae , orMoraxella catarrhalis , at age 4 weeks, was associated with
increased risk of bronchiolitis, recurrent wheeze, asthma and pneumonia,
during the first 3 years of life [20,21].
The viral etiology of
bronchiolitis, i.e. whether it was RSV or human rhinovirus (HRV)
related, was not reported in this study.
3. NASOPHARYNGEAL
MICROBIOTA COMMUNITY COMPOSITION AND RSV INFECTION