Abstract
A common strategy shared by all known gammaherpesviruses is their ability to establish a latent infection in lymphocytes – predominantly in B cells. In immunocompromised patients, such as transplant recipients or AIDS patients, gammaherpesvirus infections can lead to the development of lymphoproliferative disease and lymphoid malignancies. The human gamma-herpesviruses, EBV and KSHV, encode proteins that are capable of modulating the host immune signaling machinery, thereby subverting host immune responses. Murine gamma-herpesvirus 68 (MHV68) infection of laboratory strains of mice has proven to be useful small-animal model that shares important pathogenic strategies with the human gamma-herpesviruses. The MHV68 M2 protein is known to manipulate B cell signaling and, dependent on route and dose of virus inoculation, plays a role in both the establishment of latency and virus reactivation. M2 contains two tyrosines that are targets for phosphorylation, and have been shown to interact with the B cell signaling machinery. Here we describe in vitro and in vivo studies of M2 mutants which reveals that while both tyrosines Y120 and Y129 are required for M2 induction of IL-10 expression from primary murine B cells in vitro, only Y129 is critical for reactivation from latency and plasma cell differentiation in vivo.
Highlights
Gammaherpesviruses, members of the Herpesviridae family, are lymphotropic viruses that are characterized by their ability to establish latency in lymphocytes - in B cells
Since M2 induction of IRF4 leads to IL-10 induction in B cells, we wanted to further study the roles of the individual tyrosines of M2 in IL-10 production in a more physiological context, namely primary murine B cells
B cells were isolated from the spleens of naıve C57Bl/6 mice and transduced with the recombinant MSCV retroviruses expressing either the M2/Y120F or the M2/Y129F mutant [recombinant MSCV expressing either wild type M2 or a null mutant of M2 (M2stop; in which a translation stop codon was introduced in place of residue 13 in the M2 open reading frame) were used as positive and negative controls, respectively]
Summary
Gammaherpesviruses, members of the Herpesviridae family, are lymphotropic viruses that are characterized by their ability to establish latency in lymphocytes - in B cells. The human viruses of this family, Epstein-Barr Virus (EBV) and Kaposi’s Sarcoma associated Herpesvirus (KSHV) are associated with a range of lymphoproliferative diseases and lymphomas in immunocompromised situations (reviewed in [1]). KSHV, a member of the more common rhadinovirus genus, is the etiologic agent of AIDS-related KS, and is associated with the development of primary effusion lymphoma (PEL) and multicentric Castleman’s disease (reviewed in [3]). The strict species tropism of EBV and KSHV greatly hampers detailed studies of viral pathogenesis and host defense in vivo. Much of the in vivo studies have been accumulated from limited utilization of either small-animal models or primate models
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