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.

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

“…Further, EBV (and human herpesvirus 6 [HHV-6], when present) loads are significantly elevated in A-T patients, and abnormal EBV-driven lymphoproliferation observed early in life has been suggested as a possible diagnostic trigger for A-T (12). Consistent with the inadequate control of EBV in A-T patients, we showed that MHV68 chronic infection is poorly controlled in ATM-deficient mice, an animal model of A-T (18). The mechanism(s) by which ATM deficiency confers increased susceptibility to deregulated chronic gammaherpesvirus infection remains unclear.…”

“…Thus, in an ATM-competent host, these pro-and antiviral functions of ATM occur simultaneously, establishing a virus-host balance that both promotes and limits chronic gammaherpesvirus infection. In support of this model, we showed that ATM-deficient mice display an inadequate and skewed MHV68-specific CD8 T cell response (18). Further, myeloid cell-specific ATM deficiency attenuated establishment of MHV68 latency in vivo, likely by directly facilitating MHV68 reactivation from macrophages (19).…”

Testing for Herpesvirus Infection Is Essential in Children with Chromosomal-Instability Syndromes

“…n a set of very elegantly performed experiments, applying infection of ataxia-telangiectasia (A-T)-mutated kinase (ATM)-deficient mice with murine gammaherpesvirus 68 (MHV-68), Kulinski et al (1) have demonstrated that the function of ATM is necessary for an optimal adaptive immune response against gammaherpesvirus infection. Their data provide excellent experimental evidence for a long-standing clinical observation, namely, the puzzling fact that children with ATM deficiency (A-T disease) often show high copy numbers of Epstein-Barr virus (EBV) in their peripheral blood.…”

Role of ATM in the Formation of the Replication Compartment during Lytic Replication of Epstein-Barr Virus in Nasopharyngeal Epithelial Cells

“…In the past few years, different viruses have been reported to initiate the DNA damage response (DDR) during primary infection and lytic reactivation (18)(19)(20)(21)(22). The DNA damage response is a surveillance mechanism to monitor genome integrity and coordinate different aspects of cellular response, including cell cycle progression, gene transcription, and DNA repair.…”