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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-? ratio in respiratory secretions. The IL-4/IFN-? 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-? ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.

SUBMITTER: Caballero MT

PROVIDER: S-EPMC4319428 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Caballero Mauricio T MT Serra M Elina ME Acosta Patricio L PL Marzec Jacqui J Gibbons Luz L Salim Maximiliano M Rodriguez Andrea A Reynaldi Andrea A Garcia Alejandro A Bado Daniela D Buchholz Ursula J UJ Hijano Diego R DR Coviello Silvina S Newcomb Dawn D Bellabarba Miguel M Ferolla Fausto M FM Libster Romina R Berenstein Ada A Siniawaski Susana S Blumetti Valeria V Echavarria Marcela M Pinto Leonardo L Lawrence Andrea A Ossorio M Fabiana MF Grosman Arnoldo A Mateu Cecilia G CG Bayle Carola C Dericco Alejandra A Pellegrini Mariana M Igarza Ignacio I Repetto Horacio A HA Grimaldi Luciano Alva LA Gudapati Prathyusha P Polack Norberto R NR Althabe Fernando F Shi Min M Ferrero Fernando F Bergel Eduardo E Stein Renato T RT Peebles R Stokes RS Boothby Mark M Kleeberger Steven R SR Polack Fernando P FP

The Journal of clinical investigation 20150102 2

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 ...[more]

PMID: 25555213

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Project description:During silicosis, immune cells, including macrophages, T cells, B cells, and NK cells, participate in fibrosis development through alteration of the immune status. Dendritic cells (DCs) are professional antigen-presenting cells (APCs) with a key role in initiating immune responses and sustaining immune tolerance to maintain homeostasis. The relative contribution of DCs to silicosis progression is not well-documented. In the current study, we investigated the phenotypic and functional alterations of peripheral blood mononuclear cell (PBMC)-derived DCs of Sprague-Dawley (SD) rat during immune responses to silica exposure. We established models for direct and indirect exposure of DCs to silica by either treating DCs with silica or coculturing them with alveolar macrophages (AMs) treated with silica, respectively. The functional activity of DCs was analyzed by measuring their expression of costimulatory molecules, fluorescent microparticle uptake, cytokine production, and ability to mediate T cell polarization in vitro. In vivo, we demonstrated that silica could induce DC migration in response to silica exposure. Our results show that cytokine production by DCs was increased in response to direct silica direct exposure, while indirect silica exposure led to reduced cytokine levels. Moreover, the phagocytic capacity of DCs increased in cocultures after silica exposure. Gene and protein expression analyses showed that silica exposure altered the expression levels of Toll-like receptor pathway proteins and inflammatory factors. DC surface expression of the costimulatory molecules, CD80, CD86, and major histocompatibility complex, was inhibited by exposure to silica, which mediated a Th2-polarizing response in vitro. In rats, silica exposure induced migration of DCs from the peripheral blood into the alveoli. These results demonstrate that direct and indirect exposure to silica particles alter the phenotype and function of DCs, thereby regulating immune responses. Such changes may contribute to the development of silicosis by altering DC phenotype, function, and migration and by influencing the balance between Th1 and Th2 cells.

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

Publications

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

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