Ming Zhou, Xuan Liu, Haiqing Xiao, Zhaojie Su, Kun Wu, Longmei Zhang, Xinglin Li, Wanyun Li, Chang Zhang, Hao Li, Baojie Shi, Chaoyang Chen, Nan Xu, Jiang Li, Jinxin Miao, Yifan Hu, Huachen Zhu, Yi Guan, Tong Cheng, Ningshao Xia, Lunzhi Yuan
Over the past decades, respiratory virus infections have led to millions of cases of critical illness and deaths in humans. However, the high mutation rate of respiratory viruses greatly reduces the effectiveness of virus-target countermeasures such as vaccines and antibodies, necessitating the development of host-target immunotherapies. In a hamster model of SARS-CoV-2 infection, we observed diverse disease outcomes, delineated the variant-specific lung transcriptome landscape and demonstrated that a rational combination of pharmacological targeting of innate and adaptive immune responses is sufficient to reduce mortality and severe illness caused by beta, delta and EG.1 variants. The synergism of Poly IC-mediated activation of the innate immune response and FK506-mediated inhibition of the adaptive immune response resulted in significant suppression of both viral load and lung injury. Notably, this strategy is also available in humanized mice infected with SARS-CoV-2, H1N1 and H3N2 influenza viruses, suggesting a potent cross-virus broad-spectrum therapeutic effect.