Spred-2 negatively regulates influenza A virus (H1N1)-induced pneumonia (170.11)

Abstract

Abstract Influenza A (H1N1) viral infections have been identified as the etiologic agents for historic pandemics, and contribute to the annual mortality associated with acute viral pneumonia. Many studies have elucidated the functions of H1N1-viral proteins of this negative-strand RNA virus have been well elucidated. However, the virus-induced intracellular signaling events remain unknown. The Raf/MEK/ERK cascade is the prototype of mitogen-activated protein (MAP) kinase cascades and has an important role in cell growth, differentiation, and survival. The Sprouty-related Ena/VASP homology 1-domain-containing protein (Spred) has recently been identified as a negative regulator of Raf-dependent ERK activation. Here, we demonstrate that Spred-2-knockout (KO) mice led to higher mortality with greater virus load compared with wild-type (WT) mice during influenza A (H1N1) viral infection. In addition, Spred-2 KO mice showed more severe pneumonia with higher mRNA levels of Type-I IFNs (IFN-α and IFN-β) and pro-inflammatory cytokines (TNF-α and IL-6). Moreover, administration of MEK-inhibitor, U0126, improved mortality with lower viral load with lower mRNA levels of Type-I IFNs and pro-inflammatory cytokines. Together, the results of this study show that Spred-2 negatively regulates anti-viral immunity during H1N1 infection. We propose that Spred-2 might be a novel therapeutic target for controlling the immune response against influenza H1N1 virus infection.