Single-cell susceptibility to viral infection is driven by variable cell states

The ability of a virus to infect a cell is partly determined by host factors required for the viral life cycle. However, not every cell of a given type is equally susceptible to infection. Profiling susceptible subsets of cells could reveal additional host factors, but viral infection obscures and remodels the state of these cells prior to infection. We used single-cell clone tracing to retrospectively identify cells that were highly susceptible to infection with SARS-CoV-2. Depletion of certain factors identified by our approach revealed roles in viral entry, whereas others exerted control over the infectable cell state itself. Patient lung samples revealed heterogeneous expression of these factors in vivo, with heightened expression in particular inflammatory pathologies. We further found a distinct cell state that was susceptible to the influenza A virus. Thus, intrinsic variability in state is a major determinant of whether individual cells can be infected by a virus.