To confirm whether Spike-Fc promotes lung disease pathogenesis through increased AngII production and functional alterations of the renin-angiotensin system, the authors blocked the AngII receptor type 1 (AT1R) with a specific inhibitor. The AT1R is the crucial receptor that mediates AngII-induced vascular permeability and severe acute lung injury. Inhibition of the AT1R indeed attenuated acute severe lung injury in Spike-Fc–treated mice. Inhibition of the AT1R also attenuated pulmonary edema. Taken together, the data show that SARS-CoV Spike can exaggerate acute lung failure through deregulation of the renin-angiotensin system. Moreover, SARS-CoV Spike–mediated lung failure can be rescued by inhibition of AT1R.