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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.
Highlights
Recent outbreaks of highly pathogenic influenza A virus (IAV) infections have had important economic repercussions and have raised concerns that a new influenza pandemic will occur in the near future
Our findings reveal that TLR3À/À mice have an unexpected advantage against Influenza A virus (IAV) challenge as we show for the first time that a reduction of TLR3-mediated inflammatory response reduces the clinical manifestations of IAV-induced pneumonia
In view of this major information, we anticipated at the start of our investigation that TLR3 would act as a protective component and, its absence in TLR3À/À mice would render the animals more susceptible to IAV infection
Summary
Recent outbreaks of highly pathogenic influenza A virus (IAV) infections have had important economic repercussions and have raised concerns that a new influenza pandemic will occur in the near future. The etiological agents of the disease, the single-stranded RNA influenza viruses, are classified into three types (A, B, and C), of which influenza A is clinically the most important [1]. In the United States alone, there are more than 20,000 deaths per year, and in the large pandemic of 1918, over 20 million people died worldwide [2,3,4]. Vaccines and antiviral molecules to control influenza have been developed during the last years, the disease is by no means under control since these treatments are not available worldwide and their efficacy is not optimal [3,4,5]. A better understanding of the molecular mechanisms of IAV pathogenesis and host immune responses is required for the development of more efficient means of prevention and treatment of influenza
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