Critical role of TLR4 in human metapneumovirus mediated innate immune responses and disease pathogenesis (169.21)

Abstract

Abstract Human metapneumovirus (hMPV), described for the first time in 2001, has become one of the main viral pathogens responsible for acute respiratory tract infections in children, elderly and immunocompromised patients. The mammalian Toll-like receptors (TLR) were identified as critical regulators of innate immunity to a variety of microbes, including bacteria and fungi. Respiratory syncytial virus (RSV) fusion protein has been shown to activate TLR4, but their role in other viral infections, such as hMPV, has been largely unexplored. In this study, we examine the in vivo innate immune response in TLR4-deficient (C57BL/10ScNJ) mice and wild-type (C57BL/10SnSnJ) mice challenged with hMPV virus to address the role of TLR4 in the innate immune response to this respiratory virus infection. Our results demonstrate that mice lacking TLR4 loose less body weight compared to wild type mice. When inflammatory mediators was measured in bronchoalveolar lavage at different days post-infection, significantly lower levels of proinflammatory cytokines (IL-6, TNF-α) immunomodulatory cytokines (IL-12 p40, IL-17) and chemokines (MCP-1, MIP-1α) were detected. Further, consistent with bodyweight loss, TLR4 deficient mice show better pulmonary function demonstrated by reduced airway obstruction and airway hyperresponsiveness. The results of this study indicate that TLR4 is important for activation of the innate immune response to hMPV infection however it can also contribute to disease pathogenesis.