Caballero Mauricio T, Serra M Elina, Acosta Patricio L, Marzec Jacqui, Gibbons Luz, Salim Maximiliano, Rodriguez Andrea, Reynaldi Andrea, Garcia Alejandro, Bado Daniela, Buchholz Ursula J, Hijano Diego R, Coviello Silvina, Newcomb Dawn, Bellabarba Miguel, Ferolla Fausto M, Libster Romina, Berenstein Ada, Siniawaski Susana, Blumetti Valeria, Echavarria Marcela, Pinto Leonardo, Lawrence Andrea, Ossorio M Fabiana, Grosman Arnoldo, Mateu Cecilia G, 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, Bergel Eduardo, Stein Renato T, Peebles R Stokes, Boothby Mark, Kleeberger Steven R, Polack Fernando P
J Clin Invest. 2015 Feb;125(2):571-82. doi: 10.1172/JCI75183. Epub 2015 Jan 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 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.
虽然30%-70%感染呼吸道合胞病毒(RSV)的婴儿会患上细支气管炎,但2%的患儿需要住院治疗。目前尚不清楚为何健康的足月婴儿疾病严重程度存在差异;不过,病毒滴度、炎症和Th2偏向被认为是可能的解释。虽然Toll样受体4(TLR4)与这些疾病表型相关,但该受体在呼吸道合胞病毒(RSV)发病机制中的作用仍存在争议。在此,我们评估了TLR4与环境因素在RSV疾病中的相互作用,并确定了与重症相关的免疫介质。两组独立的RSV细支气管炎婴儿群体研究表明,RSV感染的严重程度由个体的TLR4基因型和环境中脂多糖(LPS)暴露情况决定。患有严重疾病的RSV感染婴儿表现出较高的GATA3/T-细胞β链(T-bet)比值,这在呼吸道分泌物中表现为较高的白细胞介素-4(IL-4)/干扰素-γ(IFN-γ)比值。严重RSV感染婴儿体内的IL-4/IFN-γ比值表明存在Th2极化。RSV感染的小鼠模型证实,LPS暴露、Tlr4基因型和Th2极化会影响疾病表型。本研究结果共同确定了影响RSV发病机制的环境和遗传因素,并揭示高IL-4/IFN-γ比值与重症相关。此外,这些分子应作为治疗干预的潜在靶点进行探索。