title: Gammaherpesvirus latency induces antibody-associated thrombocytopenia in mice.
abstract: Human herpesviruses establish lifelong latency. Viral recrudescence can lead to the development of cancers, immunoproliferative disorders, transplantation complications, and thrombocytopenia. Although platelet-specific autoantibodies have been reported in patients infected with the Epstein-Barr virus (EBV), the mechanisms by which thrombocytopenia is induced remain unclear, as do the relative contributions of lytic viral replication and latent viral gene expression. The human gammaherpesviruses are tightly restricted in their ability to infect other mammals, so they are difficult to study in live animal models. Here we show that infection of mice with murine gammaherpesvirus-68 (γHV68), a rodent-specific pathogen closely related to EBV, induces the production of platelet-binding antibodies and causes thrombocytopenia. Infection of antibody-deficient mice does not lead to thrombocytopenia, indicating the platelet decrease is mediated by antibody. Additionally, infection with a latency-null recombinant γHV68 does not induce thrombocytopenia, suggesting factors associated with viral latency drive the infection-induced antibody-mediated thrombocytopenia. These studies describe an important animal model of gammaherpesvirus-induced autoimmune thrombocytopenia and demonstrate that this pathology is mediated by antibody and dependent on viral latency. This model will allow studies of the underlying mechanisms of disease progression and the testing of therapeutic strategies for the alleviation of virus-induced thrombocytopenia.
authors.affiliation: Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
authors.forename: Claire E
authors.initials: CE
authors.lastname: Burkum
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Lanzer
authors.forename: Alan D
authors.initials: AD
authors.lastname: Roberts
authors.forename: Mykola
authors.initials: M
authors.lastname: Pinkevych
authors.forename: Asako
authors.initials: A
authors.lastname: Itakura
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Kummer
authors.forename: Frank M
authors.initials: FM
authors.lastname: Szaba
authors.forename: Miles P
authors.initials: MP
authors.lastname: Davenport
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
authors.forename: David L
authors.initials: DL
authors.lastname: Woodland
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smiley
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Blackman
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001791:Blood Platelet Disorders / Q000209:etiology / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000276:immunology*; D005260:Female; D018142:Gammaherpesvirinae / Q000502:physiology*; D006566:Herpesviridae Infections / Q000150:complications / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013045:Species Specificity; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D000906:Antibodies; D007148:Immunoglobulin mu-Chains