Summary The cell and tissue tropism of viruses is defined as the capacity of a virus to infect specific cells and tissues and is determined by both viral and cellular factors. An important factor for initiation of infection is cell entry, which is dependent on the ability of the virus to dock with its cognitive receptor. A growing understanding of species differences in ACE2 structure and, perhaps more importantly, in tissue specific patterns of expression has underscored the potential limitations in the use of mouse models for the study of disease pathogenesis of coronaviruses such as SARS-CoV-2 that rely on ACE2 for cellular entry. We propose to implement a strategy for the rapid generation of mouse models in which human ACE2 expression is limited to individual or multiple airway epithelial populations. Using these lines, we will examine the impact of the cellular pattern of ACE2 expression in the respiratory tract on the sequence of events following exposure to SARS-CoV2 coronavirus.