Increased susceptibility to influenza A in a mouse model of MeCP2 duplication syndrome (VIR2P.1163)

MeCP2 duplication syndrome is a devastating neurodevelopmental disorder caused by duplication of the Xq28 region of the X chromosome, primarily affecting males. Methyl-CpG-binding protein 2 (MeCP2) ubiquitously binds methylated CpG sites in the genome, and regulates gene expression by recruitment of transcriptional mediators. MeCP2 is expressed highly in both neurons and immune cells, thus mutations or over-expression of MeCP2 are associated with neurologic pathology (including seizures, motor dysfunction, and cognitive impairment), and immunologic pathology. Many patients die by the age of 25, and recurrent respiratory infections are a common cause of death. We are studying the pathogenesis of influenza A virus in a mouse model of MeCP2 overexpression, the MeCP2Tg3 mouse, which expresses MeCP2 at ~3 fold normal levels. MeCP2Tg3 mice display significant mortality approximately one week post infection, with T and B cell deficiencies in both number and activation, further characterized by high viral titer and low virus-specific antibody levels in the infected lung. Preliminary evidence suggests that vascular and/or lymphatic impairment may underlie both immunologic defects and the increased mortality observed in MeCP2Tg3 mice during influenza A virus infection. In sum, these findings uncover MeCP2 as an important regulator of host response to respiratory virus infection and may inform treatment of human patients with MeCP2 duplication syndrome.