Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

Corbett, Nathan; Blimkie, Darren; Ho, Kevin; Cai, Bing; Sutherland, Darren; Kallos, Arlene; Crabtree, Juliet; Rein‐Weston, Annie; Lavoie, Pascal M.; Turvey, Stuart E.; Hawkins, Natalie; Self, Steven G.; Wilson, Christopher; Hajjar, Adeline M.; Fortuno, Edgardo S.; Kollmann, Tobias R.

doi:10.1371/journal.pone.0015041

Cited by 156 publications

(199 citation statements)

References 36 publications

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“…DCs from adults produced stronger type I IFN responses following poly(I·C) stimulation than DCs from 1-to 2-year-old children (34). This was not observed with other TLR ligands (34). The lack of responses to poly(I·C) stimulation in DCs from children correlates with a recent study showing attenuation of type I IFN responses to RSV in children up to 5 years of age that was directly linked to RIG-I (20).…”

Section: Discussionsupporting

confidence: 66%

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Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

Taylor

Woods

Winkler

et al. 2014

J Virol

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La Crosse virus (LACV) is the major cause of pediatric viral encephalitis in the United States; however, the mechanisms responsible for age-related susceptibility in the pediatric population are not well understood. Our current studies in a mouse model of LACV infection indicated that differences in myeloid dendritic cell (mDC) responses between weanling and adult mice accounted for susceptibility to LACV-induced neurological disease. We found that type I interferon (IFN) responses were significantly stronger in adult than in weanling mice. Production of these IFNs required both endosomal Toll-like receptors (TLRs) and cytoplasmic RIG-I-like receptors (RLRs). Surprisingly, IFN expression was not dependent on plasmacytoid DCs (pDCs) but rather was dependent on mDCs, which were found in greater number and induced stronger IFN responses in adults than in weanlings. Inhibition of these IFN responses in adults resulted in susceptibility to LACV-induced neurological disease, whereas postinfection treatment with type I IFN provided protection in young mice. These studies provide a definitive mechanism for age-related susceptibility to LACV encephalitis, where mDCs in young mice are insufficiently activated to control peripheral virus replication, thereby allowing virus to persist and eventually cause central nervous system (CNS) disease. IMPORTANCE La Crosse virus (LACV) is the primary cause of pediatric viral encephalitis in the UnitedStates. Although the virus infects both adults and children, over 80% of the reported neurological disease cases are in children. To understand why LACV causes neurological disease primarily in young animals, we used a mouse model where weanling mice, but not adult mice, develop neurological disease following virus infection. We found that an early immune response cell type, myeloid dendritic cells, was critical for protection in adult animals and that these cells were reduced in young animals. Activation of these cells during virus infection or after treatment with type I interferon in young animals provided protection from LACV. Thus, this study demonstrates a reason for susceptibility to LACV infection in young animals and shows that early therapeutic treatment in young animals can prevent neurological disease.

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Section: Discussionsupporting

confidence: 66%

“…Interestingly, stimulation of human DCs with poly(I·C) also shows age-dependent responsiveness. DCs from adults produced stronger type I IFN responses following poly(I·C) stimulation than DCs from 1-to 2-year-old children (34). This was not observed with other TLR ligands (34).…”

Section: Discussionmentioning

confidence: 83%

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

Taylor

Woods

Winkler

et al. 2014

J Virol

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“…At all times, the balance between production of proand anti-inflammatory mediators is tightly regulated to allow efficient, protective immune responses to develop while preventing the pathological consequences of excessive inflammation (26). In the particular context of control of inflammatory activity in early life, a pivotal role for neonatal B cells producing IL-10 as a result of TLR9 activation has been reported (27), a role that is consistent with reports of robust TLR ligand-mediated IL-10 responses present at birth both in non-African and in African populations (28)(29)(30).…”

supporting

confidence: 53%

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

et al. 2013

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g 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. TLRmediated interleukin 6 (IL-6) and IL-10 production was robust at birth and then stabilized, whereas tumor necrosis factor alpha (TNF-␣) and gamma interferon (IFN-␥) 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-␣ 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 TLRmediated 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.

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“…Innate immune responsiveness was quantified using published techniques (18)(19)(20). Umbilical cord blood was obtained from healthy, full-term infants delivered by elective Caesarian section before the onset of labor.…”

Section: Quantifying Innate Immune Responsivenessmentioning

confidence: 99%

Functional Genetic Variation inNFKBIAand Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

Ali

Hirschfeld

Mayer

et al. 2013

The Journal of Immunology

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Respiratory diseases are the most frequent chronic illnesses in babies and children. Although a vigorous innate immune system is critical for maintaining lung health, a balanced response is essential to minimize damaging inflammation. We investigated the functional and clinical impact of human genetic variants in the promoter of NFKBIA, which encodes IκBα, the major negative regulator of NF-κB. In this study, we quantified the functional impact of NFKBIA promoter polymorphisms (rs3138053, rs2233406, and rs2233409) on promoter-driven protein expression, allele-specific and total NFKBIA mRNA expression, IκBα protein expression, and TLR responsiveness; mapped innate immune regulatory networks active during respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia; and genotyped and analyzed independent cohorts of children with respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Genetic variants in the promoter of NFKBIA influenced NFKBIA gene expression, IκBα protein expression, and TLR-mediated inflammatory responses. Using a systems biology approach, we demonstrated that NFKBIA/IκBα is a central hub in transcriptional responses of prevalent childhood lung diseases, including respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Finally, by examining independent pediatric lung disease cohorts, we established that this immunologically relevant genetic variation in the promoter of NFKBIA is associated with differential susceptibility to severe bronchiolitis following infection with respiratory syncytial virus, airway hyperresponsiveness, and severe bronchopulmonary dysplasia. These data highlight the importance of negative innate immune regulators, such as NFKBIA, in pediatric lung disease and begin to unravel common aspects in the genetic predisposition to bronchopulmonary dysplasia, bronchiolitis, and childhood asthma.

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Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

Cited by 156 publications

References 36 publications

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

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

Functional Genetic Variation inNFKBIAand Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

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