title: Interactions between innate antiviral and atopic immunoinflammatory pathways precipitate and sustain asthma exacerbations in children.
abstract: Severe asthma exacerbations in children requiring hospitalization are typically associated with viral infection and occur almost exclusively among atopics, but the significance of these comorbidities is unknown. We hypothesized that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations. To address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during exacerbation vs convalescence by microarray and flow cytometry. We demonstrate that circulating T cells manifest the postactivated "exhausted" phenotype during exacerbations, whereas monocyte/dendritic cell populations display up-regulated CCR2 expression accompanied by phenotypic changes that have strong potential for enhancing local inflammation after their recruitment to the atopic lung. Notably, up-regulation of FcepsilonR1, which is known to markedly amplify capacity for allergen uptake/presentation to Th2 effector cells via IgE-mediated allergen capture, and secondarily programming of IL-4/IL-13-dependent IL-13R(+) alternatively activated macrophages that have been demonstrated in experimental settings to be a potent source of autocrine IL-13 production. We additionally show that this disease-associated activation profile can be reproduced in vitro by cytokine exposure of atopic monocytes, and furthermore that IFN-alpha can exert both positive and negative roles in the process. Our findings suggest that respiratory viral infection in atopic children may initiate an atopy-dependent cascade that amplifies and sustains airway inflammation initiated by innate antiviral immunity via harnessing underlying atopy-associated mechanisms. These interactions may account for the unique susceptibility of atopics to severe viral-induced asthma exacerbations.
authors.affiliation: Telethon Institute for Child Health Research, and Centre for Child Health Research, Faculty of Medicine and Dentistry, The University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Lily S
authors.initials: LS
authors.lastname: Subrata
authors.forename: Joelene
authors.initials: J
authors.lastname: Bizzintino
authors.forename: Emilie
authors.initials: E
authors.lastname: Mamessier
authors.forename: Anthony
authors.initials: A
authors.lastname: Bosco
authors.forename: Katherine L
authors.initials: KL
authors.lastname: McKenna
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wikström
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: Peter D
authors.initials: PD
authors.lastname: Sly
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Hales
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Thomas
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Laing
authors.forename: Peter N
authors.initials: PN
authors.lastname: LeSouëf
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Holt
mesh_terms: D000208:Acute Disease; D000258:Adenovirus Infections, Human / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D007251:Influenza, Human / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D018184:Paramyxoviridae Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators