title: Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice.
abstract: Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively. MeCP2 plays a critical role in neuronal function and the function of cells throughout the body. It has been previously demonstrated that MeCP2 regulates T cell function and macrophage response to multiple stimuli, and that immune-mediated rescue imparts significant benefit inMecp2-null mice. Unlike Rett syndrome, MeCP2 duplication syndrome results in chronic, severe respiratory infections, which represent a significant cause of patient morbidity and mortality. Here, we demonstrate that MeCP2Tg3mice, which overexpress MeCP2 at levels 3- to 5-fold higher than normal, are hypersensitive to influenza A/PR/8/34 infection. Prior to death, MeCP2Tg3mice experienced a host of complications during infection, including neutrophilia, increased cytokine production, excessive corticosterone levels, defective adaptive immunity, and vascular pathology characterized by impaired perfusion and pulmonary hemorrhage. Importantly, we found that radioresistant cells are essential to infection-related death after bone marrow transplantation. In all, these results demonstrate that influenza A infection in MeCP2Tg3mice results in pathology affecting both immune and nonhematopoietic cells, suggesting that failure to effectively respond and clear viral respiratory infection has a complex, multicompartment etiology in the context of MeCP2 overexpression.
authors.affiliation: Center for Brain Immunology and Glia.|Department of Neuroscience.|Graduate Program in Neuroscience.|Medical Scientist Training Program.
authors.forename: James C
authors.initials: JC
authors.lastname: Cronk
authors.affiliation: Center for Brain Immunology and Glia.|Department of Neuroscience.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Herz
authors.affiliation: Beirne B. Carter Center for Immunology Research.|Department of Pathology.
authors.forename: Taeg S
authors.initials: TS
authors.lastname: Kim
authors.affiliation: Center for Brain Immunology and Glia.|Department of Neuroscience.
authors.forename: Antoine
authors.initials: A
authors.lastname: Louveau
authors.affiliation: Beirne B. Carter Center for Immunology Research.|Department of Pharmacology.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Moser
authors.affiliation: Department of Surgery.
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Center for Brain Immunology and Glia.|Department of Neuroscience.
authors.forename: Igor
authors.initials: I
authors.lastname: Smirnov
authors.affiliation: Department of Pathology.|Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Tung
authors.affiliation: Medical Scientist Training Program.|Beirne B. Carter Center for Immunology Research.|Department of Pathology.|Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Braciale
authors.affiliation: Center for Brain Immunology and Glia.|Department of Neuroscience.|Graduate Program in Neuroscience.|Medical Scientist Training Program.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kipnis
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006470:Hemorrhage / Q000209:etiology; D009980:Influenza A virus; D007371:Interferon-gamma / Q000276:immunology; D008171:Lung Diseases / Q000209:etiology; D038901:X-Linked Intellectual Disability / Q000235:genetics / Q000276:immunology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000235:genetics* / Q000276:immunology; D011836:Radiation Tolerance; D014652:Vascular Diseases / Q000209:etiology
chemical_list: D016207:Cytokines; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D007371:Interferon-gamma; D003345:Corticosterone