title: TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.
abstract: While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.
authors.forename: Mauricio T
authors.initials: MT
authors.lastname: Caballero
authors.forename: M Elina
authors.initials: ME
authors.lastname: Serra
authors.forename: Patricio L
authors.initials: PL
authors.lastname: Acosta
authors.forename: Jacqui
authors.initials: J
authors.lastname: Marzec
authors.forename: Luz
authors.initials: L
authors.lastname: Gibbons
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Salim
authors.forename: Andrea
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Andrea
authors.initials: A
authors.lastname: Reynaldi
authors.forename: Alejandro
authors.initials: A
authors.lastname: Garcia
authors.forename: Daniela
authors.initials: D
authors.lastname: Bado
authors.forename: Ursula J
authors.initials: UJ
authors.lastname: Buchholz
authors.forename: Diego R
authors.initials: DR
authors.lastname: Hijano
authors.forename: Silvina
authors.initials: S
authors.lastname: Coviello
authors.forename: Dawn
authors.initials: D
authors.lastname: Newcomb
authors.forename: Miguel
authors.initials: M
authors.lastname: Bellabarba
authors.forename: Fausto M
authors.initials: FM
authors.lastname: Ferolla
authors.forename: Romina
authors.initials: R
authors.lastname: Libster
authors.forename: Ada
authors.initials: A
authors.lastname: Berenstein
authors.forename: Susana
authors.initials: S
authors.lastname: Siniawaski
authors.forename: Valeria
authors.initials: V
authors.lastname: Blumetti
authors.forename: Marcela
authors.initials: M
authors.lastname: Echavarria
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pinto
authors.forename: Andrea
authors.initials: A
authors.lastname: Lawrence
authors.forename: M Fabiana
authors.initials: MF
authors.lastname: Ossorio
authors.forename: Arnoldo
authors.initials: A
authors.lastname: Grosman
authors.forename: Cecilia G
authors.initials: CG
authors.lastname: Mateu
authors.forename: Carola
authors.initials: C
authors.lastname: Bayle
authors.forename: Alejandra
authors.initials: A
authors.lastname: Dericco
authors.forename: Mariana
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Ignacio
authors.initials: I
authors.lastname: Igarza
authors.forename: Horacio A
authors.initials: HA
authors.lastname: Repetto
authors.forename: Luciano Alva
authors.initials: LA
authors.lastname: Grimaldi
authors.forename: Prathyusha
authors.initials: P
authors.lastname: Gudapati
authors.forename: Norberto R
authors.initials: NR
authors.lastname: Polack
authors.forename: Fernando
authors.initials: F
authors.lastname: Althabe
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.forename: Fernando
authors.initials: F
authors.lastname: Ferrero
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bergel
authors.forename: Renato T
authors.initials: RT
authors.lastname: Stein
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
authors.forename: Mark
authors.initials: M
authors.lastname: Boothby
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Polack
mesh_terms: D000818:Animals; D001990:Bronchiolitis, Viral / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012136:Respiratory Syncytial Viruses; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494748:Gata3 protein, mouse; C573415:IFNG protein, human; C508598:IL4 protein, human; D008070:Lipopolysaccharides; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D015847:Interleukin-4; D007371:Interferon-gamma