Defining host mechanisms that restrict EBV lytic reactivation - ABSTRACT
Epstein-Barr virus (EBV) is an extremely pervasive human herpesvirus, infecting approximately 95% of the global
population by adulthood. EBV is transmitted through saliva and establishes infection in the oral cavity where it
then establishes a latent infection for life in memory B cells. In most individuals this infection will remain benign,
but EBV-associated diseases include infectious mononucleosis and cancers, more commonly in immune-
compromised individuals. The balance between latent and lytic infection is under tight control and understanding
the regulation of this process has broad implications for processes ranging from viral persistence in the oral
mucosa to strategies to eliminate latently infected tumor cells. EBV reactivates in response to a diverse range of
stressors including DNA damage, hypoxia, histone deacetylase inhibitors and activation of the B-cell receptor. A
pervasive phenomenon, observed both in vitro and in vivo, is that cells have a heterogenous response to lytic
induction stimuli. In a fraction of cells, the virus fully reactivates, while others remain completely refractory or
only partially progress through the lytic cycle leading to an abortive infection. To better understand these cell
fates after EBV lytic reactivation, my lab recently completed a single-cell RNA seq experiment of resting and
reactivated EBV+ B lymphoma cells. We observed differential host gene expression patterns between refractory,
abortive, and productive lytic cells. This included high expression of the known EBV restriction factors MYC and
STAT3 in the refractory cells, but previously unknown markers of abortive cell populations: one characterized by
elevated IL-6 receptor and the other defined by pro-survival signaling through the NFB pathway. Based on our
single-cell data and prior studies, I hypothesize that an EBV induced DNA damage response leads to IL-6
production, which in turn promotes an abortive, antiviral state through the IL-6 receptor and ultimately pro-
survival NFB signaling. In addition to defining mechanisms of host defense from EBV reactivation, this work
also has important clinical ramifications as lytic induction therapies are currently in trials for EBV-associated
malignancies. Understanding host factors that restrict successful lytic reactivation could lead to more effective
therapeutic strategies in the future. Furthermore, these findings could have broad implications for how other
herpesviruses reactivate and how latently infected cells communicate to regulate this process.
