Infections In Early Life Research Articles

Tumor necrosis factor-related apoptosis-inducing ligand translates neonatal respiratory infection into chronic lung disease.

Respiratory infections in early life can lead to chronic respiratory disease. Chlamydia infections are common causes of respiratory disease, particularly pneumonia in neonates, and are linked to permanent reductions in pulmonary function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. Here we identify novel roles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting Chlamydia respiratory infection-induced pathology in early life, and subsequent chronic lung disease. By infecting TRAIL-deficient neonatal mice and using neutralizing antibodies against this factor and its receptors in wild-type mice, we demonstrate that TRAIL is critical in promoting infection-induced histopathology, inflammation, and mucus hypersecretion, as well as subsequent alveolar enlargement and impaired lung function. This suggests that therapeutic agents that target TRAIL or its receptors may be effective treatments for early-life respiratory infections and associated chronic lung disease.

Phagocytosis of neonatal pathogens by peripheral blood neutrophils and monocytes from newborn preterm and term infants

Deficiencies in phagocytosis may contribute to the increased susceptibility of infants to early life infections. Data on phagocytosis of the major neonatal pathogens Staphylococcus epidermidis (SE), Staphylococcus aureus (SA), and Escherichia coli (EC) by preterm infant leukocytes are inconsistent. Cord and <24-h peripheral blood were collected from very preterm (<30.1 wks gestational age (GA)) and term (37-42 wks GA) infants. Monocyte and neutrophil phagocytosis of pHrodo-labeled SE, SA, and EC were analyzed using a small-volume flow cytometry assay, with simultaneous characterization of surface activation marker expression. Preterm infants had lower proportions of monocytes and neutrophils capable of phagocytosis than term infants, but preterm infant phagocytes had higher phagocytic capacity. Phagocytosis was strongly correlated between cord and <24-h peripheral blood. Supplementation with exogenous complement significantly increased phagocytosis of EC but not of SE or SA. Monocyte human leukocyte antigen (HLA)-DR expression was lower in preterm infants but did not correlate with phagocytosis. There is no defect in phagocytosis by monocytes and neutrophils from preterm compared with term infants, although preterm infants possess fewer phagocytes, possibly contributing to susceptibility to bacterial infection. Further investigation into the development of postnatal phagocytic competence is warranted.

Respiratory Infections in Early Life and the Development of Islet Autoimmunity in Children at Increased Type 1 Diabetes Risk

There is evidence for a role of infections within the pathogenesis of islet autoimmunity and type 1 diabetes mellitus (T1D), but previous studies did not allow assessment of potential critical time windows in this context. To examine whether early, short-term, or cumulative exposures to episodes of infection and fever during the first 3 years of life were associated with the initiation of persistent islet autoimmunity in children at increased T1D risk. Prospective cohort study with daily infection records and regular assessment of islet autoimmunity. Diabetes Research Institute, Munich, Germany. A total of 148 children at high T1D risk with documentation of 1245 infectious events in 90,750 person-days during their first 3 years of life. Hazard ratios (HRs) for seroconversion to persistent islet autoantibodies were assessed in Cox regression models with numbers of respiratory, gastrointestinal, and other infections, adjusting for sex, delivery mode, intervention group, season of birth, and antibiotic use. An increased HR of islet autoantibody seroconversion was associated with respiratory infections during the first 6 months of life (HR = 2.27; 95% CI, 1.32-3.91) and ages 6.0 to 11.9 months (HR = 1.32; 95% CI, 1.08-1.61). During the second year of life, no meaningful effects were detected for any infectious category. A higher number of respiratory infections in the 6 months prior to islet autoantibody seroconversion was also associated with an increased HR (HR = 1.42; 95% CI, 1.12-1.80). Respiratory infections in early childhood are a potential risk factor for the development of T1D.

28. Early-life viral infection causes neuroinflammation, cognitive deficits, and changes in neurogenesis in the neonatal piglet

Environmental insults during sensitive developmental periods can affect neural cells and circuits, slow cognitive development, and increase the risk for behavioral disorders. However, the ramifications of postnatal infection on brain and cognitive development are poorly understood. Using a neonatal piglet model, we showed that infection with the porcine reproductive and respiratory syndrome virus (PRRSV), a model of viral pneumonia, caused drastic microglial cell activation within the hippocampus with 82% and 43% of microglia being MHC-II positive at 13 and 20 days post-inoculation, respectively. In control piglets, less than 5% of microglia in the hippocampus were MHC-II positive. Increased inflammatory gene expression (e.g., IL-1B, IL-6, TNFa, and IFNY) was seen across multiple brain regions including the hippocampus. In a hippocampal-dependent spatial t-maze task, PRRSV piglets took longer to acquire the task, had a longer latency to choice, and a higher total distance moved. PRRSV also affected neurogenesis in the piglet dentate gyrus. In non-infected controls there were more BrdU-positive cells in males than females. PRRSV caused a reduction in surviving cells in males, but there were no changes in females. In addition, there was a ∼30% reduction in the number of new cells that developed into mature neurons in both males and females with PRRSV. These data suggest that early-life neuroinflammation has a profound effect on brain and cognitive development.

Programming of the Lung in Early Life by Bacterial Infections Predisposes to Chronic Respiratory Disease

There is emerging evidence that chronic respiratory diseases such as asthma and emphysema may originate in early life. Respiratory infections with certain bacterial pathogens such as Chlamydia, Haemophilus influenzae and Streptococcus pneumoniae in early life may promote permanent deleterious changes in immunity, lung structure, and function that predispose to, or increase the severity of chronic respiratory diseases in later life. For example, these infections increase immune responses, which drive subsequent asthma pathogenesis. Targeting the pathways involved with specific inhibitors or agonists may prevent these consequences of early-life infection. Vaccination and immunomodulatory therapies that control the infections and their sequelae may also be efficacious.

Genetic and epigenetic susceptibility to early life infection

This review aims to interpret the current literature on the role of genetic and epigenetic factors in susceptibility to neonatal infection, a leading cause of early life mortality and morbidity. Epidemiological data indicate that the differential susceptibility to infection is partly heritable. To date there have been relatively few studies on genetic determinants of susceptibility to neonatal infection and many of these have methodological shortcomings. Most studies predominantly focus on the innate immune system. There is growing interest in the potential role of epigenetic mechanisms in disease susceptibility and data are emerging on the role of epigenetics in the maturation of the immune system in early life. Infection is a leading cause of morbidity and mortality, especially in preterm infants, but it remains unclear why neonates are so susceptible or what mediates differential risk. Genetic and epigenetic epidemiologic studies may assist in the identification of critical protective and pathogenic pathways. Despite the current relative lack of robust data, such studies may facilitate the development of interventions that ultimately decrease the significant morbidity and mortality of this highly vulnerable population.

Enterovirus infections in early childhood and the risk of atopic disease – a nested case‐control study

Enterovirus infections in childhood have been associated with a reduced risk of atopy in cross-sectional studies. To study the relation between enterovirus infections in the first 2years of life and atopic disease with IgE sensitization in a prospective study setting. This was a nested case-control study among children who had been followed from birth. Neutralizing antibodies against 12 enterovirus serotypes were analysed at the age of 2years from 71 atopic children and 142 non-atopic control children. Atopy was defined as having an atopic disease and IgE antibodies against at least one aeroallergen by the age of 5years. Cumulative exposure to different enterovirus serotypes was inversely associated with atopy [odds ratio (OR) 0.73; 95% confidence interval (CI): 0.56-0.96]. The most pronounced protection was seen when echoviruses were analysed as a separate group (OR 0.63; 95%CI: 0.46-0.88). We propose that exposure to several different enteroviruses in early childhood is inversely associated with atopic diseases. Our results support the hypothesis that repeated microbial infections in early life may protect from atopic sensitization and atopic diseases.

Malaria Modifies Neonatal and Early-Life Toll-Like Receptor Cytokine Responses

Protection from infections in early life relies extensively on innate immunity, but it is unknown whether and how maternal infections modulate infants' innate immune responses, thereby altering susceptibility to infections. Plasmodium falciparum causes pregnancy-associated malaria (PAM), and epidemiological studies have shown that PAM enhances infants' susceptibility to infection with P. falciparum. We investigated how PAM-mediated exposures in utero affect innate immune responses and their relationship with infection in infancy. In a prospective study of mothers and their babies in Benin, we investigated changes in Toll-like receptor (TLR)-mediated cytokine responses related to P. falciparum infections. Whole-blood samples from 134 infants at birth and at 3, 6, and 12 months of age were stimulated with agonists specific for TLR3, TLR4, TLR7/8, and TLR9. TLR-mediated interleukin 6 (IL-6) and IL-10 production was robust at birth and then stabilized, whereas tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses were weak at birth and then increased. In multivariate analyses, maternal P. falciparum infections at delivery were associated with significantly higher TLR3-mediated IL-6 and IL-10 responses in the first 3 months of life (P < 0.05) and with significantly higher TLR3-, TLR7/8-, and TLR9-mediated TNF-α responses between 6 and 12 months of age (P < 0.05). Prospective analyses showed that higher TLR3- and TLR7/8-mediated IL-10 responses at birth were associated with a significantly higher risk of P. falciparum infection in infancy (P < 0.05). Neonatal and infant intracellular TLR-mediated cytokine responses are conditioned by in utero exposure through PAM late in pregnancy. Enhanced TLR-mediated IL-10 responses at birth are associated with an increased risk of P. falciparum infection, suggesting a compromised ability to combat infection in early life.

Early life exposures and the risk of adult glioma

Exposure to common infections in early life may stimulate immune development and reduce the risk for developing cancer. Birth order and family size are proxies for the timing of exposure to childhood infections with several studies showing a reduced risk of glioma associated with a higher order of birth (and presumed younger age at infection). The aim of this study was to examine whether birth order, family size, and other early life exposures are associated with the risk of glioma in adults using data collected in a large clinic-based US case-control study including 889 glioma cases and 903 community controls. A structured interviewer-administered questionnaire was used to collect information on family structure, childhood exposures and other potential risk factors. Logistic regression was used to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI) for the association between early life factors and glioma risk. Persons having any siblings were at significantly lower risk for glioma when compared to those reporting no siblings (OR=0.64; 95% CI 0.44-0.93; p=0.020). Compared to first-borns, individuals with older siblings had a significantly lower risk (OR=0.75; 95% CI 0.61-0.91; p=0.004). Birth weight, having been breast fed in infancy, and season of birth were not associated with glioma risk. The current findings lend further support to a growing body of evidence that early exposure to childhood infections reduces the risk of glioma onset in children and adults.

Anti-viral agents: potential utility in exacerbations of asthma

Asthma is the most common chronic respiratory disease and its prevalence is on the increase. Respiratory viral infections in early life have been suggested to increase the risk of development of asthma in later life and virus infection remains the single greatest precipitant of asthma exacerbations. The development of effective anti-viral treatments remains a key target for therapeutic intervention. Here we discuss the role of respiratory viral infection in asthma exacerbation and highlight current and potential anti-viral agents and their mechanisms of action.

Hospitalized prenatal and childhood infections and obesity in Danish male conscripts

PurposeWe examined the relation between early life infections and adult obesity. MethodsA cohort of Danish males who underwent mandatory army fitness examinations was studied. Hospitalizations for childhood infections and their mothers' hospitalization for infection during pregnancy were identified via the Danish National Registry of Patients. The outcome was obesity (body mass index ≥ 30 kg/m2) at conscription. We calculated prevalence odds ratios (OR) and 95% confidence intervals (CI) associating the obesity with whether the conscript had a hospitalization for infection up to age 5, and separately, whether the conscript's mother was hospitalized for an infection prenatally. ResultsOf the 17,456 men, 13% had a childhood infection (8.2% of whom were obese, compared with 7.4% without childhood infection); 1.2% of conscripts were exposed to a prenatal infection (10% of whom were obese, compared with 7.4% without prenatal infection). For childhood infection, the adjusted OR was 1.21 (95% CI, 1.01–1.44); stratified analyses suggested the association may be greater among conscripts born preterm (adjusted OR, 2.08; 95% CI, 1.06–4.09), whereas among the conscripts who were full term, the adjusted OR was 1.15 (95% CI, 0.96–1.38). For prenatal infection, the adjusted OR was 1.34 (95% CI, 0.82–2.19). ConclusionsWe found a small association between both prenatal and childhood infections and prevalent obesity in early adulthood, although the results may be partly explained by unmeasured confounders.

Murine models of infectious exacerbations of airway inflammation

Airway inflammation underpins the pathogenesis of the major human chronic respiratory diseases. It is now well recognized that respiratory infections with bacteria and viruses are important in the induction, progression and exacerbation of these diseases. There are no effective therapies that prevent or reverse these events. The development and use of mouse models are proving valuable in understanding the role of infection in disease pathogenesis. They have recently been used to show that infections in early life alter immune responses and lung structure to increase asthma severity, and alter immune responses in later life to induce steroid resistance. Infection following smoke exposure or in experimental chronic obstructive pulmonary disease exacerbates inflammation and remodeling, and worsens cystic fibrosis. Further exploration of these models will facilitate the identification of new therapeutic approaches and the testing of new preventions and treatments.

Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice

Respiratory tract viruses are a major environmental risk factor for both the inception and exacerbations of asthma. Genetic defects in Toll-like receptor (TLR) 7-mediated signaling, impaired type I interferon responses, or both have been reported in asthmatic patients, although their contribution to the onset and exacerbation of asthma remains poorly understood. We sought to determine whether Pneumovirus infection in the absence of TLR7 predisposes to bronchiolitis and the inception of asthma. Wild-type and TLR7-deficient (TLR7(-/-)) mice were inoculated with the rodent-specific pathogen pneumonia virus of mice at 1 (primary), 7 (secondary), and 13 (tertiary) weeks of age, and pathologic features of bronchiolitis or asthma were assessed. In some experiments infected mice were exposed to low-dose cockroach antigen. TLR7 deficiency increased viral load in the airway epithelium, which became sloughed and necrotic, and promoted an IFN-α/β(low), IL-12p70(low), IL-1β(high), IL-25(high), and IL-33(high) cytokine microenvironment that was associated with the recruitment of type 2 innate lymphoid cells/nuocytes and increased TH2-type cytokine production. Viral challenge of TLR7(-/-) mice induced all of the cardinal pathophysiologic features of asthma, including tissue eosinophilia, mast cell hyperplasia, IgE production, airway smooth muscle alterations, and airways hyperreactivity in a memory CD4(+) T cell-dependent manner. Importantly, infections with pneumonia virus of mice promoted allergic sensitization to inhaled cockroach antigen in the absence but not the presence of TLR7. TLR7 gene defects and Pneumovirus infection interact to establish an aberrant adaptive response that might underlie virus-induced asthma exacerbations in later life.

The role of early life viral bronchiolitis in the inception of asthma

PROPOSE OF REVIEW: Cumulative evidence suggest that early life bronchiolitis is a major risk factor for subsequent wheezing episodes and asthma. The purpose of this review is to present the recent findings and current perspectives regarding the interplay between bronchiolitis and long-term respiratory outcomes. Recent studies have supported the long-recognized link between early life severe respiratory syncytial virus bronchiolitis and the physician diagnosis of asthma by school age, and this association appears to continue into early adulthood. Evidence is accumulating regarding the role of early life infection with human rhinovirus as an important antecedent for future asthma. Whether viral bronchiolitis is causal or an early manifestation of future asthma remains uncertain. Vitamin D status has emerged as a potential modifying factor for viral-induced wheeze and could potentially influence the development of asthma. Viral bronchiolitis early in life is a major and potential long-term risk factor for subsequent wheezing and asthma. Whether the association between bronchiolitis and subsequent asthma is due to causality or a reflection of predisposition may be dependent on host factors and virus-specific effects.

Childhood infectious disease and premature death from cancer: a prospective cohort study

Studies of the association between early life infections and cancer have produced inconsistent findings, possibly due to limited adjustment for confounding and retrospective designs. This study utilised data from the Newcastle Thousand Families Study, a prospective cohort of 1,142 individuals born in Newcastle-upon-Tyne in 1947, to assess the impact of various childhood infectious diseases on cancer mortality during ages 15-60 years. Detailed information was collected prospectively on a number of early life factors. Deaths from cancer during ages 15-60 years were analysed in relation to childhood infections, adjusting for potential early-life confounders, using Cox proportional-hazards regression. In a subsample who returned questionnaires at aged 49-51 years, additional adjustment was made for adult factors to predict death from cancer during ages 50-60 years. Childhood history of measles and influenza, were both independently associated with lower cancer mortality during ages 15-60 years (adjusted hazard ratios = 0.39, 95% CI 0.17-0.88 and 0.49, 95% CI 0.24-0.98 respectively). In contrast, childhood pertussis was associated with higher cancer mortality during ages 15-60 years (adjusted hazard ratio = 4.88, 95% CI 2.29-10.38). In the subsample with additional adjustment for adult variables, measles and pertussis remained significantly associated with cancer mortality during ages 50-60 years. In this pre-vaccination cohort, childhood infection with measles and influenza were associated with a reduced risk of death from cancer in adulthood, while pertussis was associated with an increased risk. While these results suggest some disease-specific associations between early-life infections and cancer, further studies are required to confirm the specific associations identified.

Epidemiology of human atopic dermatitis – seven areas of notable progress and seven areas of notable ignorance

This narrative review highlights areas within the epidemiology of human atopic dermatitis (AD) where significant progress has been made and where considerable ignorance still exists. The review is supported by systematic reviews wherever possible, with the purpose of stimulating fresh approaches to human and veterinary research into AD. Areas of progress include valid and repeatable methods of disease definition, global documentation of disease prevalence and impact, clarification of the role of some genetic factors, such as filaggrin gene mutations, clear evidence that environmental factors are key, as demonstrated by the positive social class gradient and rising prevalence, a possible protective effect of infections in early life, documentation of comorbidities, such as a reduced risk of glioma, and mapping the evidence base through systematic reviews and an online global resource of clinical trials. Areas where significant uncertainty still exists include the question of whether AD is more than one disease, the tendency for researchers to look at the same old risk factors, lack of specific environmental risk factors that are amenable to manipulation, inconsistencies in the hygiene hypothesis, sparse knowledge about adult AD, lack of evidence that eczema can be prevented, and little scientific work exploring what causes flares in people with established AD.

Vaccination against influenza in pregnant women – safety and effectiveness

Influenza is a major cause of morbidity and mortality worldwide. During seasonal influenza epidemics and pandemics, pregnancy places otherwise healthy women at an increased risk of complications from influenza. The factors believed to increase the susceptibility of complicated influenza infection during pregnancy are linked to the physiologic changes, including immunologic changes (attenuation of the cell-mediated immune responses, selective suppression of T-helper 1 cell mediated immunity while the adaptive humoral immunity remains unimpaired), increased cardiac output and oxygen consumption and tidal volume. Pregnant women have similar incidence of seasonal influenza as the general population, however because of the physiological changes, they are at an increased risk of complications (including secondary pneumonia, acute respiratory insufficiency increased risk of stillbirth, premature deliveries) and death. Immunization of pregnant women against influenza is currently recommended in many countries. Vaccination against influenza with trivalent inactivated vaccine (TIV) has been proven to be safe and effective. Lack of harmful effect of TIV on pregnant women and newborns has been demonstrated in several studies: no increased risk of spontaneous abortions, preterm birth, low birth weight, congenital malformations, cesarean section have been reported. Vaccination against influenza has been proven to be effective in reducing rates and severity of the disease in vaccinated mothers and their children. Several studies revealed a decreased risk of influenza-like illnesses among mothers who were vaccinated during pregnancy but also a decreased risk of laboratory confirmed cases of influenza and hospitalizations due to influenza and its complications among newborns and infants born to vaccinated mothers. Currently available inactivated influenza vaccines are not licensed for use in infants younger than 6 months. Protection of young infants against the infection in early life thus requires a cocooning strategy to reduce the number of vulnerable individuals among care givers and contacts. Neonates and infants may be also protected against influenza directly by antibodies of maternal origin that cross the placenta or are transferred via breast milk. The duration of passively acquired antibodies depends on the initial blood concentration and is probably less than 6 months. Vaccine coverage among pregnant women rdmains low Possible explanations include lack of education by health care workers, the feeling among the general public that influenza is not a serious problem, and the failure of prenatal care providers to offer the vaccine. Overall, the most important factor for a woman to decide to be immunized during pregnancy was to have a clear recommendation from the health care provider Reasons evoked by obstetricians for not providing influenza vaccines included lack sufficient data on safety and efficacy concerns about the medical legal risks of vaccination during pregnancy and the perdeption that pregnant women would not want to be vaccinated. Educational intervention targeting health care workers in charge of pregnant women should be primary implemented to provide higher influenza vaccine coverage and to protect pregnant women and young infants from influenza related morbidity

Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma

SUMMARYDevelopment of asthma in childhood is linked to viral infections of the lower respiratory tract in early life, with subsequent chronic exposure to allergens. Progression to persistent asthma is associated with a Th2-biased immunological response and structural remodelling of the airways. The underlying mechanisms are unclear, but could involve epigenetic changes. To investigate this, we employed a recently developed mouse model in which self-limited neonatal infection with a pneumovirus, followed by sensitisation to ovalbumin via the respiratory tract and low-level chronic challenge with aerosolised antigen, leads to development of an asthmatic phenotype. We assessed expression of microRNA by cells in the proximal airways, comparing changes over the period of disease progression, and used target prediction databases to identify genes likely to be up- or downregulated as a consequence of altered regulation of microRNA. In parallel, we assessed DNA methylation in pulmonary CD4+ T cells. We found that a limited number of microRNAs exhibited marked up- or downregulation following early-life infection and sensitisation, for many of which the levels of expression were further changed following chronic challenge with the sensitizing antigen. Targets of these microRNAs included genes involved in immune or inflammatory responses (e.g. Gata3, Kitl) and in tissue remodelling (e.g. Igf1, Tgfbr1), as well as genes for various transcription factors and signalling proteins. In pulmonary CD4+ T cells, there was significant demethylation at promoter sites for interleukin-4 and interferon-γ, the latter increasing following chronic challenge. We conclude that, in this model, progression to an asthmatic phenotype is linked to epigenetic regulation of genes associated with inflammation and structural remodelling, and with T-cell commitment to a Th2 immunological response. Epigenetic changes associated with this pattern of gene activation might play a role in the development of childhood asthma.

Advances in adult asthma diagnosis and treatment in 2012: Potential therapeutics and gene-environment interactions

In the Journal of Allergy and Clinical Immunology in 2012, research reports related to asthma in adults clustered around mechanisms of disease, with a special focus on their potential for informing new therapies. There was also consideration of the effect of the environment on health from pollution, climate change, and epigenetic influences, underlining the importance of understanding gene-environment interactions in the pathogenesis of asthma and response to treatment.

The HLA-G low expressor genotype is associated with protection against bipolar disorder

Implication of immune processes in bipolar disorder (BD) has recently gained increasing attention. Tolerogenic molecules, among which HLA-G plays a prominent role, mediate the modulation of such processes. The HLA-G locus is characterized by a high number of polymorphisms including a functionally relevant 14 base pair (bp) insertion/deletion (Ins/Del) allele affecting the HLA-G expression. Here, we analyzed the distribution of this polymorphism in 561 BD patients and 161 healthy and found that the HLA-G 14bp Ins/Ins genotype was significantly more prevalent in healthy controls than in patients (corrected p; pc=0.032) and that the prevalence of such protective genotype is lower among patients born during the winter season as compared to those born in other periods (pc=0.006). Possible mechanisms between low HLA G expression and resistance to infections as well as potential relationships between infections in early life and susceptibility to BD are discussed.