Acute lung injury (ALI) leading to
acute respiratory distress syndrome is the major cause of
COVID-19 lethality. Cell entry of SARS-CoV-2 occurs via the interaction between its surface spike
protein (SP) and
angiotensin-converting enzyme-2 (ACE2). It is unknown if the viral spike
protein alone is capable of altering lung vascular permeability in the lungs or producing
lung injury in vivo. To that end, we intratracheally instilled the S1 subunit of
SARS-CoV-2 spike protein (S1SP) in K18-hACE2 transgenic mice that overexpress human ACE2 and examined signs of COVID-19-associated
lung injury 72 h later. Controls included K18-hACE2 mice that received saline or the intact SP and wild-type (WT) mice that received S1SP. K18-hACE2 mice instilled with S1SP exhibited a decline in
body weight, dramatically increased white blood cells and
protein concentrations in bronchoalveolar lavage fluid (BALF), upregulation of multiple inflammatory
cytokines in BALF and serum, histological evidence of
lung injury, and activation of
signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways in the lung. K18-hACE2 mice that received either saline or SP exhibited little or no evidence of
lung injury. WT mice that received S1SP exhibited a milder form of
COVID-19 symptoms, compared with the K18-hACE2 mice. Furthermore, S1SP, but not SP, decreased cultured human pulmonary microvascular transendothelial resistance (TER) and barrier function. This is the first demonstration of a COVID-19-like response by an essential virus-encoded
protein by SARS-CoV-2 in vivo. This model of COVID-19-induced ALI may assist in the investigation of new therapeutic approaches for the management of
COVID-19 and other coronaviruses.