1. TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.
- Author
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Caballero MT, Serra ME, Acosta PL, Marzec J, Gibbons L, Salim M, Rodriguez A, Reynaldi A, Garcia A, Bado D, Buchholz UJ, Hijano DR, Coviello S, Newcomb D, Bellabarba M, Ferolla FM, Libster R, Berenstein A, Siniawaski S, Blumetti V, Echavarria M, Pinto L, Lawrence A, Ossorio MF, Grosman A, Mateu CG, Bayle C, Dericco A, Pellegrini M, Igarza I, Repetto HA, Grimaldi LA, Gudapati P, Polack NR, Althabe F, Shi M, Ferrero F, Bergel E, Stein RT, Peebles RS, Boothby M, Kleeberger SR, and Polack FP
- Subjects
- Animals, Disease Models, Animal, Female, GATA3 Transcription Factor genetics, GATA3 Transcription Factor immunology, Humans, Infant, Infant, Newborn, Interferon-gamma genetics, Interferon-gamma immunology, Interleukin-4 genetics, Interleukin-4 immunology, Male, Mice, T-Box Domain Proteins genetics, T-Box Domain Proteins immunology, Th2 Cells pathology, Bronchiolitis, Viral genetics, Bronchiolitis, Viral immunology, Bronchiolitis, Viral pathology, Environmental Exposure adverse effects, Genotype, Lipopolysaccharides toxicity, Respiratory Syncytial Virus Infections genetics, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections pathology, Respiratory Syncytial Viruses, Th2 Cells immunology, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 immunology
- 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.
- Published
- 2015
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