title: Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia.
abstract: 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.
authors.affiliation: Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Le Goffic
authors.forename: Viviane
authors.initials: V
authors.lastname: Balloy
authors.forename: Micheline
authors.initials: M
authors.lastname: Lagranderie
authors.forename: Lena
authors.initials: L
authors.lastname: Alexopoulou
authors.forename: Nicolas
authors.initials: N
authors.lastname: Escriou
authors.forename: Richard
authors.initials: R
authors.lastname: Flavell
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
mesh_terms: D000208:Acute Disease; D000818:Animals; D001980:Bronchi / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D009980:Influenza A virus; D007700:Kinetics; D007962:Leukocytes / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011024:Pneumonia, Viral / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000821:virology*; D011650:Pulmonary Alveoli / Q000473:pathology; D016019:Survival Analysis; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D015854:Up-Regulation; D019562:Viral Load
chemical_list: D018836:Inflammation Mediators; D051196:Toll-Like Receptor 3