CYTOKINE SIGNALING REGULATES MULTIPLE STAGES OF GAMMA-HERPESVIRUS INFECTION IN MYELOID CELLS
TL;DR
It is demonstrated that IFNγ blocks lytic replication through at least two distinct mechanisms, restricting delivery to or stability of the viral genome in the nucleus and potently restricting lytic cycle progression downstream of the immediate-early viral transactivator, RTA.
Abstract
The gammaherpesviruses, including Epstein-Barr Virus and Kaposi’s Sarcoma-associated Herpesvirus, establish lifelong infections by maintaining a balance between lytic and latent infection states. How this balance is regulated in myeloid cells, an important but understudied cell type that can achieve both infection states, remains unclear. Using the murine gammaherpesvirus 68 (MHV68) model, we show that IFNγ and IL-4 reciprocally regulate lytic infection in macrophages in a time- and JAK/STAT signaling dependent-manner, with basal JAK/STAT signaling further restricting lytic infection. Using a combination of MHV68 reporter viruses, cellular and molecular techniques, we demonstrate that IFNγ blocks lytic replication through at least two distinct mechanisms, restricting delivery to or stability of the viral genome in the nucleus and potently restricting lytic cycle progression downstream of the immediate-early viral transactivator, RTA. These findings define specific points during lytic infection where IFNγ to enforce restricted, latent-like infection in myeloid cells. Graphical Abstract Highlights IL-4 and IFNγ reciprocally regulate MHV68 macrophage infection in a time-dependent manner Lytic replication is induced by the JAK1/JAK2 inhibitor Ruxolitinib IFNγ regulates MHV68 infection at two distinct stages IFNγ pre-treatment limits viral nuclear entry