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Immunoinflammatory responses to febrile lower respiratory infections in infants display uniquely complex/intense transcriptomic profiles

2019; Elsevier BV; Volume: 144; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2019.07.043

1097-6825

Anya C. Jones, Denise Anderson, Sally Galbraith, Emmanuelle Fantino, Diana Gutierrez Cardenas, James F. Read, Michael Serralha, Barbara J. Holt, Deborah H. Strickland, Peter D. Sly, Anthony Bosco, Patrick G. Holt,

IL-33, ST2, and ILC Pathways

In a recent birth cohort study published in the Journal of Allergy and Clinical Immunology,1Holt P.G. Mok D. Panda D. Renn L. Fabozzi G. de Klerk N.H. et al.Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.J Allergy Clin Immunol. 2019; 143: 1176-1182.e5Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar we observed a high level of variation among children in postnatal development of type 1/type 3 IFN (T1/3IFN) response capacity as measured by in vitro stimulation of PBMC responses to the viral mimic polyI:C. At birth, the mean response capacity (defined here as the number of IFN subtypes expressed) in the cohort investigated was 2.6 ± 3.2 (range, 0-14) of the 17 innate IFN genes tested, and low response capacity was associated with increased risk for persistent wheeze/asthma at age 5 years,1Holt P.G. Mok D. Panda D. Renn L. Fabozzi G. de Klerk N.H. et al.Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.J Allergy Clin Immunol. 2019; 143: 1176-1182.e5Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar and for febrile lower respiratory tract infections (fLRTIs) before age 1 year,1Holt P.G. Mok D. Panda D. Renn L. Fabozzi G. de Klerk N.H. et al.Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.J Allergy Clin Immunol. 2019; 143: 1176-1182.e5Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar the latter being a recognized risk factor for early onset asthma.2Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (582) Google Scholar, 3Holt P.G. Rowe J. Kusel M. Parsons F. Hollams E.M. Bosco A. et al.Toward improved prediction of risk for atopy and asthma among preschoolers: a prospective cohort study.J Allergy Clin Immunol. 2010; 125 (659.e1-659.e7): 653-659Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 4Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (85) Google Scholar We also showed that the range of T1/3IFNs activated in polyI:C responses in most children expanded markedly between birth and age 4 years.1Holt P.G. Mok D. Panda D. Renn L. Fabozzi G. de Klerk N.H. et al.Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.J Allergy Clin Immunol. 2019; 143: 1176-1182.e5Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar As part of earlier studies on this cohort,2Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (582) Google Scholar, 3Holt P.G. Rowe J. Kusel M. Parsons F. Hollams E.M. Bosco A. et al.Toward improved prediction of risk for atopy and asthma among preschoolers: a prospective cohort study.J Allergy Clin Immunol. 2010; 125 (659.e1-659.e7): 653-659Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar we had collected detailed respiratory infection histories on all subjects, and we used these data to test whether the frequency and/or type of infections experienced during infancy influenced this immune maturation process.1Holt P.G. Mok D. Panda D. Renn L. Fabozzi G. de Klerk N.H. et al.Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.J Allergy Clin Immunol. 2019; 143: 1176-1182.e5Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar We stratified children into subgroups by infant infection history and compared the breadth of their T1/3IFN responses at age 4 years, and the subgroup who experienced fLRTIs during year 1 stood out as the most immunocompetent by age 4 years on the basis of the number of IFN genes activated via polyI:C (∼4-fold expansion relative to responses at birth).1Holt P.G. Mok D. Panda D. Renn L. Fabozzi G. de Klerk N.H. et al.Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.J Allergy Clin Immunol. 2019; 143: 1176-1182.e5Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar This association was higher for fLRTIs than for any other infant infection category including wheezy LRTIs.1Holt P.G. Mok D. Panda D. Renn L. Fabozzi G. de Klerk N.H. et al.Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.J Allergy Clin Immunol. 2019; 143: 1176-1182.e5Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In addition, we have shown that the association between infant LRTI and risk for persistent wheeze/asthma in this cohort is generally stronger for fLRTIs than for other infection categories.1Holt P.G. Mok D. Panda D. Renn L. Fabozzi G. de Klerk N.H. et al.Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.J Allergy Clin Immunol. 2019; 143: 1176-1182.e5Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 4Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (85) Google Scholar, 5Teo S.M. Mok D. Pham K. Kusel M. Serralha M. Troy N. et al.The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.Cell Host Microbe. 2015; 17: 704-715Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar These findings suggest that fever may be a marker of respiratory infectious disease events with particularly potent immunomodulatory properties. To test this possibility, we recruited infants (<18 months, n = 15) at presentation with symptoms of acute viral bronchiolitis in the Royal Children's Hospital Emergency Department, Brisbane, Australia (see Table E1 in this article's Online Repository at www.jacionline.org). We stratified subjects on the basis of the presence of fever (≥38.0°C; “any” fLRTI as a binary variable) at the acute emergency visit. Peripheral blood was obtained at the acute visit and after recovery at convalescence 8.8 ± 2.5 weeks later. Transcriptomic profiling (RNA-Seq) was carried out on PBMCs contrasting the gene expression patterns at the acute and convalescent visits in a paired design using DESeq2 analysis (see this article's Online Repository at www.jacionline.org). Comparisons of groups derived by stratification of infected infants on the basis of the presence of fever at presentation (n = 8) versus no fever (n = 7) demonstrated 1939 differentially expressed genes (DEGs; 1176 upregulated/736 downregulated; Fig 1, A, left panel; see Table E2 in this article's Online Repository at www.jacionline.org) in the febrile group, versus a much lower number of 23 DEGs (12 upregulated/11 downregulated; see Table E3 in this article's Online Repository at www.jacionline.org) in infants without fever. We repeated this comparison adjusting for differences in viral pathogens in the 2 groups, and this conclusion remained unchanged (not shown). In contrast, stratification by wheeze at presentation demonstrated much narrower intragroup variation and less complex responses (with/without wheeze: 358/205 DEGs, respectively), marking fever as a stronger index of underlying host inflammatory response complexity/intensity. To enable more detailed comparative analyses of response profiles in febrile versus nonfebrile groups, we reduced stringency in DESeq2 analyses for infants without fever (to adjusted P value = .5), resulting in identification of 155 DEGs (65 upregulated/90 downregulated; Fig 1, A, right panel; see Table E4 in this article's Online Repository at www.jacionline.org). We then interrogated the DEGs for enrichment of biological pathways using InnateDB (see this article's Online Repository at www.jacionline.org). In infants with fever, the DEGs were enriched for T1IFN signaling, cytokine signaling, osteoclast differentiation, cell cycle, binding/uptake of ligands by scavenger receptors, and endogenous TLR signaling, whereas in infants without fever, DEGs were enriched for pathways associated with chemokines/chemokine receptor interactions and cytokine signaling (Fig 1, B). To identify putative upstream regulators of the DEGs, we used Ingenuity Systems Upstream Regulator Analysis (see this article's Online Repository at www.jacionline.org). In infants with fever, the top-ranking drivers identified were LPS (composite microbial-inflammation–associated gene signature), T1/3IFNs (including the transcriptional regulators signal transducer and activator of transcription 1/IRF7), inflammation-associated regulators (TNF, IL6, IL1B, TGM2), and TH2 (IL4 and IL13; Fig 1, C). In infants without fever, the top-ranking drivers were inflammatory-related (TREM1, LPS, TNF), and also included IFN-A but not other T1IFN-associated signatures (Fig 1, C). Of particular note are the much stronger P values and correspondingly higher activation Z scores for putative drivers of transcriptomic responses in the infected infants with fever. Despite the large differences in overall DEGs between the study groups, the small sample size mandates that caution must be exercised in interpretation of (in particular) qualitative differences between respective transcriptomes, and this issue should be addressed in follow-up studies with larger numbers of subjects. Notwithstanding this limitation, these preliminary findings collectively are consistent with fever being a marker for LRTIs that provoke maximally intense and complex host immunoinflammatory responses in infants, consistent with the role of this class of infections as strong drivers of both immune maturation1Holt P.G. Mok D. Panda D. Renn L. Fabozzi G. de Klerk N.H. et al.Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.J Allergy Clin Immunol. 2019; 143: 1176-1182.e5Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar (viz a viz the “Hygiene Hypothesis”6Strachan D.P. Family size, infection and atopy: the first decade of the “hygiene hypothesis”.Thorax. 2000; 55: S2-S10Crossref PubMed Google Scholar) and of the initial phase of asthma pathogenesis,3Holt P.G. Rowe J. Kusel M. Parsons F. Hollams E.M. Bosco A. et al.Toward improved prediction of risk for atopy and asthma among preschoolers: a prospective cohort study.J Allergy Clin Immunol. 2010; 125 (659.e1-659.e7): 653-659Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 4Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (85) Google Scholar the latter via mediation of airway tissue damage during the crucial early postnatal window period of rapid lung growth and differentiation.7Holt P.G. Sly P.D. Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment.Nat Med. 2012; 18: 726-735Crossref PubMed Scopus (201) Google Scholar The implications of these findings are 2-fold. First, prospective asthma cohort studies rarely include collection of comprehensive data on fever associated with infant LRTIs, and instead default principally to wheeze as the preferred marker of asthma-risk–associated LRTIs: we suggest that fever-related data may provide crucial additional information that could enhance the value of future epidemiological and mechanistic studies in this area. In particular, more detailed characterization of the cellular and molecular networks underlying these febrile responses in infants may provide insight into the molecular mechanisms that drive postnatal immune maturation, and as such provide guidance toward development of immune-enhancing therapeutics for use in infants genetically at “high risk” of asthma/allergy in whom the kinetics of this maturation process are sluggish relative to the rest of the population.8Holt P.G. Clough J.B. Holt B.J. Baron-Hay M.J. Rose A.H. Robinson B.W. et al.Genetic ‘risk’ for atopy is associated with delayed postnatal maturation of T-cell competence.Clin Exp Allergy. 1992; 22: 1093-1099Crossref PubMed Scopus (245) Google Scholar Download .docx (.02 MB) Help with docx files Online Repository text Download .docx (.05 MB) Help with docx files Tables E1-E4