Immune and Epigenetic Regulation Through Histone-Lysine N-methyltransferase Setdb2 During Severe Influenza Virus Infection

Influenza virus causes acute respiratory infections that are highly contagious, and leads to significant morbidity and mortality in humans and animals. Especially, the main severe pathogenesis following influenza virus infection are secondary bacterial pneumonia (SBP) and influenza-associated encephalopathy (IAE). Thus, a better understanding of the molecular mechanisms of these diseases is essential. In our studies, microarray analysis demonstrated that influenza virus infected cells such as epithelial cells and macrophages upregulated SET domain, bifurcated 2 (Setdb2) expression following influenza virus infection via type-I IFN dependent manner. Setdb2 is a histone methyltransferase that methylates Lys-9 of histone H3 (H3K9), correlated with repression of transcription. Setdb2 expression in both influenza virus pneumonia and IAE models was significantly increased compared to control mice. Next, we investigated the role of Setdb2 in both SBP and IAE models. In SBP model, knocking down Setdb2 increased amphiregulin expression, which plays a critical role in tissue homeostasis of lungs and in decreased mortality of coinfection. In IAE model, the expression of Caveolin-1, one of the key proteins that correlate with protection of the blood-brain barrier, was significantly lower in brains from the IAE group compared with the control group. Furthermore, chromatin immunoprecipitation revealed that methylation of histone H3K9 was correlated with repression of the Caveolin-1 promoter region. These studies support the idea that an understanding of epigenetic change, especially via Setdb2, during influenza virus infection can provide mechanistic approaches for controlling and modifying the immune response in SBP and IAE.