032 The Toll-like receptor (TLR)-3 médiates influenza A virus-induced acute pneumonia

Introduction Influenza is a highly contagious acute respiratory disease that causes considerable mortality every year. The etiological agent is the ssRNA influenza A virus (LAV). IAV is a major health challenge due to antigenic variation and animal reservoirs. Although vaccines and antiviral substances to control influenza have been developed, these treatments are not available Worldwide and their efficacy is not optimal. Therefore, research work on the pathogenesis of influenza infection and analysis of host immune response against the virus are still needed. Recently, we demonstrated that the innate immunity receptor TLR3 and its signaling-associated molecule TRIF play a key role in the immune response of respiratory epithelial cells to IAV ( J Biol Chem 2005 ; 280 : 5571). Here, we evaluated the role of TLR3 in influenza-mediated acute pneumonia using an experimental animal model. Methods Wild-type and TLR3-/- mice were infected by 300 pfu influenza A/Scotland/20/74(H3N2) virus and the time-course of several dynamic parameters were assessed, including animal mortality and weight, leukocyte recruitment into the airspaces, increase of alveolocapillar permeability and secretion of critical mediators. Results We first showed that expression of TLR3 in the lungs of mice is constitutive and markedly up-regulated following IAV infection. Remarkably, TLR3-/- mice were significantly more resistant (28% survival) to an IAV lethal challenge than wild-type animals (0% survival). Next, the respiratory distress index Penh and total protein amount as well as the secretion of inflammatory mediators were evaluated in the BAL fluids of TLR3-/- and wild-type animals at Day 3 post-infection (this time point was chosen as it corresponds to the peak of the viral load in the lungs of both animal groups). The Penh index was significantly diminished in TLR3-deficient mice compared to control mice, i e . 0.95 ± 0.12 vs . 1.74 + 0.2, respectively. Likewise, total protein, RANTES, IL-12 and IL-6 amounts were significantly higher in wild-type than in TLR3-/- mice. Paradoxically, while control animals had almost cleared the virus from their lungs at day 9 post-infection, the virus persisted in TLR3-I - mice (»300 times above that of wild-type mice). Conclusions TLR3 contributes to the debilitating effects of a detrimental immune response triggered by IAV infection. The current investigation suggests that a strategy to regulate or inhibit TLR3 might be of therapeutic potential during influenza pneumonia.