Susceptibility to recombinant SARS‐CoV‐2 spike protein entry in the lungs of high‐fat diet‐induced obese mice

Abstract Coronavirus disease 2019 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Obesity is a major risk factor for the development of COVID‐19. Angiotensin‐converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS‐CoV‐2. The receptor‐binding domain of the S1 subunit (S1‐RBD protein) in the SARS‐CoV‐2 spike glycoprotein binds to ACE2 on host cells, through which the virus enters several organs, including the lungs. Considering these findings, recombinant ACE2 might be utilized as a decoy protein to attenuate SARS‐CoV‐2 infection. Here, we examined whether obesity increases ACE2 expression in the lungs and whether recombinant ACE2 administration diminishes the entry of S1‐RBD protein into lung cells. We observed that high‐fat diet‐induced obesity promoted ACE2 expression in the lungs by increasing serum levels of LPS derived from the intestine. S1‐RBD protein entered the lungs specifically through ACE2 expressed in host lungs and that the administration of recombinant ACE2 attenuated this entry. We conclude that obesity makes hosts susceptible to recombinant SARS‐CoV‐2 spike proteins due to elevated ACE2 expression in lungs, and this model of administering S1‐RBD protein can be applied to new COVID‐19 treatments.