info:eu-repo/semantics/article
TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization
Fecha
2015-02Registro en:
Caballero, Mauricio Tomás; Serra, M. Elina; Acosta, Patricio Leandro; Marzec, Jacqui; Gibbons, Luz; et al.; TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization; American Society for Clinical Investigation; Journal of Clinical Investigation; 125; 2; 2-2015; 571-582
0021-9738
CONICET Digital
CONICET
Autor
Caballero, Mauricio Tomás
Serra, M. Elina
Acosta, Patricio Leandro
Marzec, Jacqui
Gibbons, Luz
Salim, Maximiliano
Rodriguez, Andrea
Reynaldi, Andrea
Garcia, Alejandro
Bado, Daniela
Buchholz, Ursula J.
Hijano, Diego Raúl
Coviello, Silvina Andrea
Newcomb, Dawn
Bellabarba, Miguel
Ferolla, Fausto Martín
Libster, Romina Paula
Berenstein, Ada
Siniawaski, Susana
Blumetti, Valeria
Echavarría, Marcela Silvia
Pinto, Leonardo
Lawrence, Andrea
Ossorio, Maria Fabiana
Grosman, Arnoldo
Mateu, Cecilia Gabriela
Bayle, Carola
Dericco, Alejandra
Pellegrini, Mariana
Igarza, Ignacio
Repetto, Horacio A.
Grimaldi, Luciano Alva
Gudapati, Prathyusha
Polack, Norberto R.
Althabe, Fernando
Shi, Min
Ferrero, Fernando Claudio
Bergel, Eduardo
Stein, Renato T.
Peebles, R. Stokes
Boothby, Mark
Kleeberger, Steven R.
Polack, Fernando Pedro
Resumen
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.