title: Ataxia telangiectasia mutated kinase controls chronic gammaherpesvirus infection.
abstract: Gammaherpesviruses, such as Epstein-Barr virus (EBV), are ubiquitous cancer-associated pathogens that interact with DNA damage response, a tumor suppressor network. Chronic gammaherpesvirus infection and pathogenesis in a DNA damage response-insufficient host are poorly understood. Ataxia-telangiectasia (A-T) is associated with insufficiency of ataxia-telangiectasia mutated (ATM), a critical DNA damage response kinase. A-T patients display a pattern of anti-EBV antibodies suggestive of poorly controlled EBV replication; however, parameters of chronic EBV infection and pathogenesis in the A-T population remain unclear. Here we demonstrate that chronic gammaherpesvirus infection is poorly controlled in an animal model of A-T. Intriguingly, in spite of a global increase in T cell activation and numbers in wild-type (wt) and ATM-deficient mice in response to mouse gammaherpesvirus 68 (MHV68) infection, the generation of an MHV68-specific immune response was altered in the absence of ATM. Our finding that ATM expression is necessary for an optimal adaptive immune response against gammaherpesvirus unveils an important connection between DNA damage response and immune control of chronic gammaherpesvirus infection, a connection that is likely to impact viral pathogenesis in an ATM-insufficient host.
authors.affiliation: Microbiology and Molecular Genetics, Medical College of Wisconsin Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Kulinski
authors.forename: Steven M
authors.initials: SM
authors.lastname: Leonardo
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Mounce
authors.forename: Laurent
authors.initials: L
authors.lastname: Malherbe
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gauld
authors.forename: Vera L
authors.initials: VL
authors.lastname: Tarakanova
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000276:immunology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D005434:Flow Cytometry; D018142:Gammaherpesvirinae; D006566:Herpesviridae Infections / Q000201:enzymology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases