All work in my section began in February 2017, so there are no CCR-based accomplishments to report yet. Nonetheless, the goals and objectives of the project have crystallized. Our preliminary work using rapamycin on transformed epithelial cell lines has revealed that mTOR inhibition confers a 4- to 20-fold enhancement of infection, depending on the nature of the virus challenge and, specifically, the route of virus entry into cells. Furthermore, we found that the rapamycin-dependent enhancement of infection is reversed by inhibitors of endosomal acidification (v-ATPase), revealing that the enhancement requires active degradation of cellular factors via the lysosomal pathway. We are currently determining whether the effect on cellular susceptibility is directly linked to macroautophagy, a catabolic process controlled by mTOR. Moreover, we plan to inhibit the PI3K-Akt-mTOR pathway upstream and downstream of mTOR to narrow down the cellular proteins directly implicated in the control of virus infection in these settings.
