TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization
Mauricio T. Caballero, … , Steven R. Kleeberger, Fernando P. Polack
Mauricio T. Caballero, … , Steven R. Kleeberger, Fernando P. Polack
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(2):571-582. https://doi.org/10.1172/JCI75183.
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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

Mauricio T. Caballero, M. Elina Serra, Patricio L. Acosta, Jacqui Marzec, Luz Gibbons, Maximiliano Salim, Andrea Rodriguez, Andrea Reynaldi, Alejandro Garcia, Daniela Bado, Ursula J. Buchholz, Diego R. Hijano, Silvina Coviello, Dawn Newcomb, Miguel Bellabarba, Fausto M. Ferolla, Romina Libster, Ada Berenstein, Susana Siniawaski, Valeria Blumetti, Marcela Echavarria, Leonardo Pinto, Andrea Lawrence, M. Fabiana Ossorio, Arnoldo Grosman, Cecilia G. Mateu, Carola Bayle, Alejandra Dericco, Mariana Pellegrini, Ignacio Igarza, Horacio A. Repetto, Luciano Alva Grimaldi, Prathyusha Gudapati, Norberto R. Polack, Fernando Althabe, Min Shi, Fernando Ferrero, Eduardo Bergel, Renato T. Stein, R. Stokes Peebles, Mark Boothby, Steven R. Kleeberger, Fernando P. Polack

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Figure 1

Pattern recognition receptors and environmental interactions.

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Pattern recognition receptors and environmental interactions. (A) LPS co...
(A) LPS concentrations categorized as low (<48 EU/ml), medium (48–480 EU/ml), and high (>480 EU/ml), as determined using an LAL assay in cradles and bed sheets of infants from low- versus middle-SES groups. P < 0.01 by Fisher’s exact test. (B) Diversity of NP colonization, defined as carriage of all 3 S. pneumoniae, H. influenzae, and M. catarrhalis bacteria in a convenience sample of 100 infants of low SES versus those of high SES. Percentage of infants with detectable bacterial DNA. P < 0.001 by χ2 test. (C and D) Association of the TLR4 Asp299Gly heterozygous genotype in RSV-infected infants with mild (white bars) or severe (black bars) bronchiolitis in groups of infants from rural homes with high NP bacterial carriage, indicators of low SES, exposure to high environmental levels of LPS (High LPS), and groups of infants from urban homes with low NP bacterial carriage, middle-SES status, and low LPS exposure levels (Low LPS) in 2003–2006 (C; P = 0.003 for interaction) and 2010–2013 (D; P = 0.002 for interaction). (E) ORs and 95% CIs for disease severity in infants from high and low LPS level environments in population 1 (2003–2006), population 2 (2010–2013), and both populations combined (P < 0.001 for interaction in combination). Fisher’s exact and Zelen’s exact tests for C–E (see Table 1). (F) CD14 C-159T and (G) CD14 C-550T alleles in RSV-infected infants with severe (black bars) or mild (white bars) bronchiolitis in groups exposed to low or high environmental levels of LPS. Fisher’s exact; P = NS for both alleles.