Gammaherpesviruses cause important diseases in immunosuppressed populations, which is due to their ability to establish a latent infection in B lymphocytes. We have learned much about viral gene expression and manipulation of host cell biology during latency. However there is still a notable gap in our knowledge regarding host cell factors required for the efficient establishment of latent infection in vivo. Our research has discovered that mice lacking microRNA-155 (miR-155) have a marked defect in their ability to establish latent infection following murine gammaherpesvirus infection. In this application we will determine the mechanism for this effect, as this will increase our understanding of host cell factors required for efficient latent infection by gammaherpesviruses in an authentic in vivo environment. In our first Specific Aim, we will test whether miR- 155 is acting in a B cell intrinsic fashion, and examine its effect on latent infection and reactivation from latency. We will also determine the molecular mechanisms underlying the effect of miR-155 on latency. The second Specific Aim examines the role of miR-155 in follicular helper CD4 T cell differentiation and function, as this cell type has been shown to be essential for the amplification of latent MHV-68 infection. In the third Specific Aim we will determine whether miR-155 is necessary chronic disease mediated by MHV-68. These experiments will provide important in vivo and mechanistic data to complement current in vitro evidence for a critical role for miR-155 in latent infection with the human gammaherpesviruses. Our data will also reveal whether miR-155 is a potential target that could be manipulated therapeutically to reduce latent virus burden in individuals at risk of severe gammaherpesvirus-related disease.
Gammaherpesvirus infections can cause life-threatening disease in immune suppressed patients. Therefore patients with AIDS, those undergoing organ transplantation, and some cancer patients are at risk of developing tumors as a result of these infections. Infection of B lymphocytes by gammaherpesviruses leads to latent infection and cellular immortalization, predisposing these cells to grow as tumors if they are not controlled by the immune response. This proposal addresses the role of a host microRNA, miR-155, in latent infection by gammaherpesviruses. This may be a valuable therapeutic target to reduce viral latency, and therefore reduce the risk of disease in susceptible patients.
| Crepeau, Rebecca L; Zhang, Peisheng; Usherwood, Edward J (2016) MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency. J Virol 90:7811-21 |
