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Publication : TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.

First Author  Caballero MT Year  2015
Journal  J Clin Invest Volume  125
Issue  2 Pages  571-82
PubMed ID  25555213 Mgi Jnum  J:220399
Mgi Id  MGI:5634616 Doi  10.1172/JCI75183
Citation  Caballero MT, et al. (2015) TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization. J Clin Invest 125(2):571-82
abstractText  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-gamma ratio in respiratory secretions. The IL-4/IFN-gamma 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-gamma ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.
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