The Intersection between Cell-Intrinsic Innate Immunity and Metabolic Sensing

我所在部门的所有工作都是从2017年2月开始的，因此目前还没有基于CCR的成果可供报告。尽管如此，该项目的目标和目的已经具体化。我们在转化的上皮细胞系上使用雷帕霉素的初步工作表明，抑制mTOR可以使感染增加4-20倍，这取决于病毒挑战的性质，特别是病毒进入细胞的途径。此外，我们发现雷帕霉素依赖的感染增强可以被内体酸化抑制物(v-ATPase)逆转，这表明这种增强需要通过溶酶体途径主动降解细胞因子。我们目前正在确定这种对细胞易感性的影响是否直接与宏观自噬有关，宏观自噬是一种由mTOR控制的分解代谢过程。此外，我们计划抑制mTOR上游和下游的PI3K-Akt-mTOR途径，以缩小在这些环境中直接参与病毒感染控制的细胞蛋白。

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.