Antiviral IFN-γ responses of monocytes at birth predict respiratory tract illness in the first year of life

doi:10.1016/j.jaci.2012.02.033

Journal of Allergy and Clinical Immunology

Volume 129, Issue 5, May 2012, Pages 1267-1273.e1

https://doi.org/10.1016/j.jaci.2012.02.033 Get rights and content

Background

Viral respiratory tract infections are the leading cause of acute illness during infancy and are closely linked to chronic inflammatory airway diseases later in life. However, the determinants of susceptibility to acute respiratory tract infections still need to be defined.

Objective

We investigated whether the individual variation in antiviral response at birth determines the risk for acute respiratory tract illness in the first year of life.

Methods

We studied 82 children who were enrolled in a birth cohort study of inner-city children with at least 1 parent with allergy or asthma. We cultured cord blood monocytes and assessed IFNG and CCL5 mRNA production at 24 hours after inoculation with respiratory syncytial virus. We also monitored the frequency of acute respiratory tract illness at 3-month intervals and analyzed nasal lavage samples for respiratory tract viruses at the time of illness during the first year.

Results

Respiratory tract infection was reported for 88% of subjects, and respiratory tract viruses were recovered in 74% of symptomatic children. We observed a wide range of antiviral responses in cord blood monocytes across the population. Furthermore, a decrease in production of IFNG (but not CCL5) mRNA in response to respiratory syncytial virus infection of monocytes was associated with a significant increase in the frequency of upper respiratory tract infections (r = −0.42, P < .001) and the prevalence of ear and sinus infections, pneumonias, and respiratory-related hospitalizations.

Conclusion

Individual variations in the innate immune response to respiratory tract viruses are detectable even at birth, and these differences predict the susceptibility to acute respiratory tract illness during the first year of life.

Section snippets

Study population

We analyzed cord blood samples from 82 newborns enrolled in the Urban Environment and Childhood Asthma (URECA) study. This group represents a subset of the 178 children enrolled at the St Louis site, which in turn was a subset of the total number of children enrolled at the Baltimore, Boston, and New York city sites between February 2005 and March 2007, as described previously.16, 17, 18 Subjects were required to have at least 1 parent with allergic rhinitis, eczema, and/or asthma and to reside

Subjects' demographics and first-year outcomes

We processed all cord blood samples that contained an adequate number of cells, representing 82 of the total of 178 children who were enrolled at the St Louis site of the URECA cohort. Among the 82 newborns, 85% of the babies were African American, the mean age of the mother at the time of delivery was 23.7 years, and 63% of the infants had at least 1 parent with asthma (Table I). Subjects were reported to have an average of 4.2 upper respiratory tract infections (colds), 1.3 wheezing

Discussion

In this study we provide evidence that a decreased antiviral interferon response at the time of birth is selectively associated with an increase in acute respiratory tract infections in the first year of life among infants at high risk for asthma and allergic disease. In support of this relationship between antiviral response and respiratory tract infection, we show that (1) RSV-driven induction of IFNG mRNA production in cord blood monocytes is variable among infants at birth; (2) decreased

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Responsiveness of immune cells to infectious stimuli at birth is known to be highly variable between subjects.31 Stronger neonatal cytokine responses, in particular for IFN-γ, have been associated with reduced respiratory tract illness,32-34 as well as with the incidence of wheeze, allergy, and asthma11-13,35,36 later in childhood. In addition, lower expression levels of TLRs on cord blood immune cells has been linked to maternal allergy.37,38
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Cord blood samples from neonates born to mothers supplemented with 4400 IU/d (n = 26) or 400 IU/d (n = 25) of vitamin D₃ were analyzed for immune cell composition by flow cytometry, Toll-like receptor (TLR) expression by quantitative PCR, and cytokine secretion after stimulation with mitogenic, TLR, and T-cell stimuli by cytometric bead array. Responsiveness to the glucocorticoid dexamethasone was determined.
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Vitamin D exposure during fetal development influences the immune system of the neonate, which can contribute to protection from asthma-related, including infectious, outcomes in early life.
Patterns of immune development in urban preschoolers with recurrent wheeze and/or atopy
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In URECA, there were no significant associations between interferon responses at birth or age 1 and the development of wheezing or atopy. Of note, we previously reported in a subset of URECA infants that IFN-γ responses of monocytes (isolated from PBMC) were inversely related to several respiratory outcomes including prevalence of upper respiratory illnesses, ear and sinus infections, and respiratory hospitalizations.27 These findings suggest that monocyte-lineage cell responses may be particularly important to regulation of wheezing illnesses, and this concept is consistent with findings from array-based measurements of PBMC during acute wheezing illnesses in asthma,28 as well as findings in animal models of viral respiratory illness.29
Disadvantaged urban children have high rates of allergic diseases and wheezing, which are diseases associated with type 2–biased immunity.
We sought to determine whether environmental exposures in early life influence cytokine responses that affect the development of recurrent wheezing illnesses and allergic sensitization.
A birth cohort of 560 urban families was recruited from neighborhoods with high rates of poverty, and 467 (83%) children were followed until 3 years of age. Cytokine responses were measured in blood cell samples obtained at birth (cord blood) and ages 1 and 3 years. Cytokine responses were examined in relation to personal characteristics and environmental exposures to allergens and endotoxin and to the development of allergic sensitization and recurrent wheeze assessed at age 3 years.
Cytokine responses generally increased with age, but responses at birth were poorly predictive for those at ages 1 and 3 years. Exposure to certain allergens (cockroach, mouse, dust mite) was significantly associated with enhanced cytokine responses at age 3 years, including IFN-α and IL-10 responses to certain stimulants and responses to phytohemagglutinin. Regarding the clinical outcomes, reduced LPS-induced IL-10 responses at birth were associated with recurrent wheeze. In contrast, reduced respiratory syncytial virus–induced IL-8 responses and increased 5′—cytosine—phosphate—guanine—3′ (CpG)-induced IL-12p40 and allergen-induced IL-4 responses were associated with atopy.
These findings suggest that diverse biologic exposures, including allergens and endotoxin, in urban homes stimulate the development of cytokine responses in early life, and that cytokine responses to specific microbial and viral stimuli are associated with the development of allergic sensitization and recurrent wheeze.
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Childhood asthma develops from a complex interaction among host and environmental factors in early life. Birth cohort studies have provided valuable insight into asthma risk factors and the natural history of wheezing and asthma through childhood and beyond. Early life aeroallergen sensitization and wheezing illnesses associated with virus and bacterial infections have been identified as pivotal risk factors for asthma inception. Recently, focus has turned toward protective factors that promote lung health in children. Studies in a variety of environments, including farms and urban communities, suggest that diverse exposures to microbes in early life lead to a lower risk of allergy and asthma in childhood. The mechanisms underlying how these exposures and the gut and airway microbiomes alter the host response to allergens and viruses are of interest and an area of ongoing study. Longitudinal follow up of birth cohorts in diverse environments worldwide will continue to provide critical knowledge about the factors that impact the natural history of asthma.
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Prenatal exposure to tobacco smoke can cause decreased levels of cord blood interferon-γ, and continued environmental tobacco smoke exposure has been shown to suppress interferon-γ levels through 11 years of age.59,61 Alteration in interferon-γ production may be particularly relevant for infection risk; Sumino and colleagues62 correlated decreased monocyte interferon production at birth with increased risk of early life infection. In addition to decreasing interferon-γ levels, in utero smoke increases the levels of cytokines associated with Th2 immune profiles.
Tobacco smoke and nicotine exposure during prenatal and postnatal life can impair lung development, alter the immune response to viral infections, and increase the prevalence of wheezing during childhood. The following review examines recent discoveries in the fields of lung development and tobacco and nicotine exposure, emphasizing studies published within the last 5 years. In utero tobacco and nicotine exposure remains common, occurring in approximately 10% of pregnancies within the United States. Exposed neonates are at increased risk for diminished lung function, altered central and peripheral respiratory chemoreception, and increased asthma symptoms throughout childhood. Recently, genomic and epigenetic risk factors, such as alterations in DNA methylation, have been identified that may influence the risk for long-term disease. This review examines the impact of prenatal tobacco and nicotine exposure on lung development with a particular focus on nicotinic acetylcholine receptors. In addition, this review examines the role of prenatal and postnatal tobacco smoke and nicotine exposure and its association with augmenting infection risk, skewing the immune response toward a T-helper type 2 bias and increasing risk for developing an allergic phenotype and asthmalike symptoms during childhood. Finally, this review outlines the respiratory morbidities associated with childhood secondhand smoke and nicotine exposure and examines genetic and epigenetic modifiers that may influence respiratory health in infants and children exposed to in utero or postnatal tobacco smoke.

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: Supported by grants from the National Institutes of Health (National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute).

: Disclosure of potential conflict of interest: K. Sumino has received research support from the National Institutes of Health (NIH). J. E. Gern is on the scientific advisory board for and owns stock options in 3V Biosciences; has consulted for Centocor, Boeheringer Ingelheim, GlaxoSmithKline, Biota, MedImmune, and Theraclone; and has received research support from AstraZeneca. G. R. Bloomberg has received research support from the NIH/National Institute of Allergy and Infectious Diseases. M. J. Holtzman has consulted for and received research support from Hoffman–La Roche and Forest Laboratories. The rest of the authors declare that they have no relevant conflicts of interest.

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Asthma and lower airway diseaseAntiviral IFN-γ responses of monocytes at birth predict respiratory tract illness in the first year of life

Background

Objective

Methods

Results

Conclusion

Section snippets

Study population

Subjects' demographics and first-year outcomes

Discussion

Curr Opin Immunol

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

Lancet

Adv Immunol

J Allergy Clin Immunol

The World Health Report 2005: make every mother and child count

Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children

Am J Respir Crit Care Med

Tucson Children's Respiratory Study: 1980 to present

J Allergy Clin Immunol

Day care attendance in the first year of life and illnesses of the upper and lower respiratory tract in children with a familial history of atopy

Pediatrics

Prospective study of healthcare utilisation and respiratory morbidity due to RSV infection in prematurely born infants

Thorax

Influence of attendance at day care on the common cold from birth through 13 years of age

Arch Pediatr Adolesc Med

Respiratory syncytial virus infection: immune response, immunopathogenesis, and treatment

Clin Microbiol Rev

Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis

Lancet

Cytokine response patterns, exposure to viruses, and respiratory infections in the first year of life

Am J Respir Crit Care Med

Cord blood cytokines and acute lower respiratory illnesses in the first year of life

Pediatrics

Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life

Thorax

Virus-inducible expression of a host chemokine gene relies on replication-linked mRNA stabilization

Proc Natl Acad Sci U S A

Asthma and lower airway disease
Antiviral IFN-γ responses of monocytes at birth predict respiratory tract illness in the first year of life