Detrimental Contribution of the Toll-Like Receptor (TLR)3 to Influenza A Virus–Induced Acute Pneumonia

PLoS Pathogens

Mustapha Si-Tahar¹  Michel Chignard²  Viviane Balloy³  Lena Alexopoulou³  Nicolas Escriou⁴  Ronan Le Goffic⁵  Micheline Lagranderie⁵  Richard Flavell⁶ 

[1] CNRS, UMR6102, Marseille, France;INSERM U631, Marseille, France;INSERM, E336, Paris, France;Institut Pasteur, Département de Médecine Moléculaire, Paris, France;Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France;Université de la Méditerranée, Faculté des Sciences de Luminy, Centre d'Immunologie de Marseille-Luminy (CIML), Marseille, France

关键词: Influenza A virus;    Toll-like receptors;    Influenza;    Respiratory infections;    Inflammation;    Mouse models;    Cytokines;    T cells;   

DOI  :  10.1371/journal.ppat.0020053

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Influenza A virus (IAV) is the etiological agent of a highly contagious acute respiratory disease that causes epidemics and considerable mortality annually. Recently, we demonstrated, using an in vitro approach, that the pattern recognition Toll-like receptor (TLR)3 plays a key role in the immune response of lung epithelial cells to IAV. In view of these data and the fact that the functional role of TLR3 in vivo is still debated, we designed an investigation to better understand the role of TLR3 in the mechanisms of IAV pathogenesis and host immune response using an experimental murine model. The time-course of several dynamic parameters, including animal survival, respiratory suffering, viral clearance, leukocyte recruitment into the airspaces and secretion of critical inflammatory mediators, was compared in infected wild-type and TLR3−/− mice. First, we found that the pulmonary expression of TLR3 is constitutive and markedly upregulated following influenza infection in control mice. Notably, when compared to wild-type mice, infected TLR3−/− animals displayed significantly reduced inflammatory mediators, including RANTES (regulated upon activation, normal T cell expressed and secreted), interleukin-6, and interleukin-12p40/p70 as well as a lower number of CD8+ T lymphocytes in the bronchoalveolar airspace. More important, despite a higher viral production in the lungs, mice deficient in TLR3 had an unexpected survival advantage. Hence, to our knowledge, our findings show for the first time that TLR3-IAV interaction critically contributes to the debilitating effects of a detrimental host inflammatory response.

【 授权许可】

CC BY