Defining the sentinel state of macrophages and its role in intrinsic antiviral immunity

Most viral infections resolve asymptomatically, suggesting immune mechanisms that preserve tissue homeostasis. Macrophages in their sentinel state restrict viral replication through intrinsic, interferon-independent mechanisms that remain poorly defined. The central hypothesis of this project is that the sentinel state is an actively maintained program, not a passive baseline, and that its coordinated dismantling enables safe macrophage activation. We identified GAS7 as a factor sustaining sentinel features including intrinsic antiviral resistance. GAS7 degradation accompanies inflammatory activation, and its genetic perturbation allows isolated study of sentinel mechanisms without confounding activation. This project will: (1) define transcriptional, metabolic, and translational features conferring intrinsic resistance; (2) dissect regulated exit during activation and dysregulated exit by HIV-1; (3) test sentinel state importance in Dengue infection in vivo. This work may inform therapeutic strategies reinforcing intrinsic defenses and vaccine designs transiently modulating these barriers.