Sexual dimorphism of COVID-19 inspires drug repositioning and host-targeting immunotherapy for viral pneumonia.

Sexual hormones play an important role in modulating disease outcome of COVID-19. The interplay between viral replication, host immune responses, pathology process and sexual hormone levels are complicated, and the underlying mechanisms remain exclusive. Here, we reveal the dose-dependent manner and multi-faceted role of the male hormone testosterone in hamster model of COVID-19 by evaluations of manifestations including survival rate, body weight loss, viral load, immune responses and lung injury. Both low and high doses of testosterone treatment cause more severe illness in male hamsters. Low dose of testosterone is beneficial for female hamsters, but high dose is harmful. Therefore, we evaluate the therapeutic effect of the testosterone inhibitor finasteride in male hamsters and demonstrate that it is sufficient to prevent death and severe pneumonia caused by different SARS-CoV-2 strains. Moreover, pulmonary transcriptome data reveals key clues for the mechanisms of testosterone-mediated disease enhancement and finasteride therapy.