The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined ...the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs. Most infants were initially colonized with Staphylococcus or Corynebacterium before stable colonization with Alloiococcus or Moraxella. Transient incursions of Streptococcus, Moraxella, or Haemophilus marked virus-associated ARIs. Our data identify the NP microbiome as a determinant for infection spread to the lower airways, severity of accompanying inflammatory symptoms, and risk for future asthma development. Early asymptomatic colonization with Streptococcus was a strong asthma predictor, and antibiotic usage disrupted asymptomatic colonization patterns. In the absence of effective anti-viral therapies, targeting pathogenic bacteria within the NP microbiome could represent a prophylactic approach to asthma.
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•The nasopharynx microbiome of infants has a simple structure dominated by six genera•Microbiome composition affects infection severity and pathogen spread to lower airways•Early asymptomatic colonization with Streptococcus increases risk of asthma•Antibiotic usage disrupts asymptomatic colonization patterns
Teo et al. characterize bacterial and viral communities within the infant nasopharynx during the first year of life, comparing between asymptomatic colonization and episodes of acute respiratory infections. Microbiome composition affects infection severity and spread to lower airways and risk for future asthma development.
Background Vitamin D (25(OH)D) deficiency has been implicated as a possible risk factor for asthma development, but studies at selected time points measuring 25(OH)D levels during childhood have ...yielded conflicting findings. Prospective studies tracking 25(OH)D levels during the initiation phase of asthma in early childhood have not been reported. Objective We sought to elucidate relationships between 25(OH)D levels from birth to age 10 years and susceptibility to allergic sensitization, respiratory tract infections, and asthma. Methods Asthma-, allergy-, and respiratory tract infection–associated phenotypes (including pathogen identification) were characterized in a high-risk birth cohort. Plasma 25(OH)D concentrations were quantified at birth and at clinical follow-ups at the ages of 0.5, 1, 2, 3, 4, 5, and 10 years, and relationships with clinical outcomes were examined. Results Cross-sectional analyses demonstrated inverse associations between 25(OH)D concentrations and the risk for concurrent sensitization at age 0.5, 2, and 3 years, and mixed-effects regression demonstrated inverse longitudinal associations of 25(OH)D levels with both sensitization and eczema. Multivariate regression modeling suggested that the number of 25(OH)D-deficient follow-ups was positively associated with risk for asthma/wheeze, eczema, and sensitization at 10 years; adjustment for sensitization (particularly by 2 years) in the asthma/wheeze models reduced 25(OH)D associations with these latter outcomes. 25(OH)D levels were also inversely associated with early nasopharyngeal colonization with Streptococcus species and age of first febrile lower respiratory illness, both of which are known asthma risk factors. Conclusion 25(OH)D deficiency in early childhood is associated with increased risk for persistent asthma, potentially through modulating susceptibility to early allergic sensitization, upper respiratory tract colonization with bacterial pathogens, or both. These relationships are only evident if 25(OH)D status is monitored prospectively and longitudinally.
Repeated cycles of infection-associated lower airway inflammation drive the pathogenesis of persistent wheezing disease in children. In this study, the occurrence of acute respiratory tract illnesses ...(ARIs) and the nasopharyngeal microbiome (NPM) were characterized in 244 infants through their first five years of life. Through this analysis, we demonstrate that >80% of infectious events involve viral pathogens, but are accompanied by a shift in the NPM toward dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change frequently precedes the detection of viral pathogens and acute symptoms. Colonization of illness-associated bacteria coupled with early allergic sensitization is associated with persistent wheeze in school-aged children, which is the hallmark of the asthma phenotype. In contrast, these bacterial genera are associated with “transient wheeze” that resolves after age 3 years in non-sensitized children. Thus, to complement early allergic sensitization, monitoring NPM composition may enable early detection and intervention in high-risk children.
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•Six genera dominate airway microbiota from birth to 2 years, but diversifies thereafter•Acute respiratory illness associates with pathogenic bacteria in the airway microbiota•Pathogenic airway bacteria may precede viral incursions and acute respiratory illness•Colonization with pathogens predicts chronic wheeze in allergic-sensitized children
Teo et al. characterize nasopharyngeal microbiota (NPM) in 244 children from birth to age 5 years during periods of illness and health. NPM colonization with illness-associated bacteria may promote acute respiratory illness independent of viral infection, and is associated with chronic or transient wheeze in allergic-sensitized or non-sensitized children, respectively.
Macrophages are dynamic cells that mature under the influence of signals from the local microenvironment into either classically (M1) or alternatively (M2) activated macrophages with specific ...functional and phenotypic properties. Although the phenotypic identification of M1 and M2 macrophages is well established in mice, this is less clear for human macrophages. In addition, the persistence and reversibility of polarized human phenotypes is not well established. Human peripheral blood monocytes were differentiated into uncommitted macrophages (M0) and then polarized to M1 and M2 phenotypes using LPS/IFN-γ and IL-4/IL-13, respectively. M1 and M2 were identified as CD64(+)CD80(+) and CD11b(+)CD209(+), respectively, by flow cytometry. Polarized M1 cells secreted IP-10, IFN-γ, IL-8, TNF-α, IL-1β, and RANTES, whereas M2 cells secreted IL-13, CCL17, and CCL18. Functionally, M2 cells were highly endocytic. In cytokine-deficient medium, the polarized macrophages reverted back to the M0 state within 12 days. If previously polarized macrophages were given the alternative polarizing stimulus after 6 days of resting in cytokine-deficient medium, a switch in polarization was seen (i.e., M1 macrophages switched to M2 and expressed CD11b(+)CD209(+) and vice versa). In summary, we report phenotypic identification of human M1 and M2 macrophages, their functional characteristics, and their ability to be reprogrammed given the appropriate stimuli.
Prospective birth cohort studies tracking asthma initiation and consolidation in community cohorts have identified viral infections occurring against a background of allergic sensitization to ...aeroallergens as a uniquely potent risk factor for the expression of acute severe asthma-like symptoms and for the ensuing development of asthma that can persist through childhood and into adulthood. A combination of recent experimental and human studies have suggested that underlying this bipartite process are a series of interactions between antiviral and atopic inflammatory pathways that are mediated by local activation of myeloid cell populations in the airway mucosa and the parallel programming and recruitment of their replacements from bone marrow. Targeting key components of these pathways at the appropriate stages of asthma provides new opportunities for the treatment of established asthma but, more crucially, for primary and secondary prevention of asthma during childhood.
To determine the association between maternal serum 25(OH)-vitamin D concentrations during a critical window of fetal neurodevelopment and behavioral, emotional, and language outcomes of offspring.
...Serum 25(OH)-vitamin D concentrations of 743 Caucasian women in Perth, Western Australia (32°S) were measured at 18 weeks pregnancy and grouped into quartiles. Offspring behavior was measured with the Child Behavior Checklist at 2, 5, 8, 10, 14, and 17 years of age (n range = 412-652). Receptive language was assessed with the Peabody Picture Vocabulary Test-Revised at ages 5 (n = 534) and 10 (n = 474) years. Raw scores were converted to standardized scores, incorporating cutoffs for clinically significant levels of difficulty.
χ(2) analyses revealed no significant associations between maternal 25(OH)-vitamin D serum quartiles and offspring behavioral/emotional problems at any age. In contrast, there were significant linear trends between quartiles of maternal vitamin D levels and language impairment at 5 and 10 years of age. Multivariate regression analyses, incorporating a range of confounding variables, found that the risk of women with vitamin D insufficiency (≤46 nmol/L) during pregnancy having a child with clinically significant language difficulties was increased close to twofold compared with women with vitamin D levels >70 nmol/L.
Maternal vitamin D insufficiency during pregnancy is significantly associated with offspring language impairment. Maternal vitamin D supplementation during pregnancy may reduce the risk of developmental language difficulties among their children.
Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci ...(eQTLs) in resting myeloid cells and CD4
T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases.
Developments over the last 5 to 10 years, principally from studies on comprehensively phenotyped prospective birth cohorts, have highlighted the important role of viral respiratory tract infections ...during infancy and early childhood, particularly those occurring against a background of pre-existing sensitization to perennial aeroallergens, in driving the development of early-onset atopic asthma. Although debate surrounding the mechanism or mechanisms governing this causal pathway remains intense, demonstration of the capacity of pretreatment with anti-IgE antibody to blunt seasonal virus-associated asthma exacerbations in children provides strong support for the underlying concept. However, emerging data appear set to further complicate this picture. Notably, a combination of culture-based studies and complementary population-wide bacterial metagenomic data suggests that parallel host-bacteria interactions during infancy might play an additional role in modulating this causal pathway, as well as contributing independently to pathogenesis. These and related issues surrounding development of immune competence during the crucial early postnatal period, when these pathways are maximally active, are discussed below.
Advances in metagenomics, proteomics, metabolomics, and systems biology are providing a new emphasis in research; interdisciplinary work suggests that personalized medicine is on the horizon. These ...advances are illuminating sophisticated interactions between human-associated microbes and the immune system. The result is a transformed view of future prevention and treatment of chronic noncommunicable diseases, including allergy. Paradigm-shifting gains in scientific knowledge are occurring at a time of rapid global environmental change, urbanization, and biodiversity losses. Multifactorial and multigenerational implications of total environmental exposures, the exposome, require coordinated interdisciplinary efforts. It is clear that the genome alone cannot provide answers to urgent questions. Here we review the historical origins of exposome research and define a new concept, the metaexposome, which considers the bidirectional effect of the environment on human subjects and the human influence on all living systems and their genomes. The latter is essential for human health. We place the metaexposome in the context of early-life immune functioning and describe how various aspects of a changing environment, especially through microbiota exposures, can influence health and disease over the life course.
Background Severe lower respiratory infections (LRIs) and atopic sensitization have been identified as independent risk factors for asthma. Objective The nature of potential interactions between ...these risk factors was the subject of this study. Methods A community-based cohort of 198 children at high atopic risk was followed from birth to 5 years. All episodes of acute respiratory illness in the first year were recorded and postnasal aspirates were collected for viral identification. History of wheeze and asthma was collected annually, and atopy was assessed at 6 months, 2 years, and 5 years. Results A total of 815 episodes of acute respiratory illness were reported, and 33% were LRIs. Viruses were detected in 69% of aspirates, most commonly rhinoviruses (48.3%) and respiratory syncytial virus (10.9%). At 5 years, 28.3%(n = 56) had current wheeze, and this was associated with wheezy odds ratio (OR), 3.4 (1.2-9.7); P = .02 and/or febrile LRI OR, 3.9 (1.4-10.5); P = .007, in particular those caused by respiratory syncytial virus or rhinoviruses OR, 4.1 (1.3-12.6); P = .02. Comparable findings were made for current asthma. Strikingly these associations were restricted to children who displayed early sensitization (≤2 years old) and not observed in nonatopic patients or those sensitized later. Conclusion These data suggest viral infections interact with atopy in infancy to promote later asthma. Notably the occurrence of both of these events during this narrow developmental window is associated with maximal risk for subsequent asthma, which suggests a contribution from both classes of inflammatory insults to disease pathogenesis. Clinical implications Protection of “high-risk” children against the effects of severe respiratory infections during infancy may represent an effective strategy for primary asthma prevention. The potential benefits of these strategies merit more careful evaluation in this age group.
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