SARS-CoV-2 ORF8 is a viral cytokine regulating immune responses
Masako Kohyama, Tatsuya Suzuki, Wataru Nakai, Chikako Ono, Sumiko Matsuoka, Koichi Iwatani, Yafei Liu, Yusuke Sakai, Atsushi Nakagawa, Keisuke Tomii, Koichiro Ohmura, Masato Okada, Yoshiharu Matsuura, Shiro Ohshima, Yusuke Maeda, Toru Okamoto, Hisashi Arase
Abstract
Many patients with severe COVID-19 suffer from pneumonia and the elucidation of the mechanisms underlying the development of this severe condition is important. The in vivo function of the ORF8 protein secreted by SARS-CoV-2 is not well understood. Here, we analyzed the function of ORF8 protein by generating ORF8-knockout SARS-CoV-2 and found that the lung inflammation observed in wild-type SARS-CoV-2-infected hamsters was decreased in ORF8-knockout SARS-CoV-2-infected hamsters. Administration of recombinant ORF8 protein to hamsters also induced lymphocyte infiltration into the lungs. Similar pro-inflammatory cytokine production was observed in primary human monocytes treated with recombinant ORF8 protein. Furthermore, we demonstrated that the serum ORF8 protein levels are well-correlated with clinical markers of inflammation. These results demonstrated that the ORF8 protein is a SARS-CoV-2 viral cytokine involved in the immune dysregulation observed in COVID-19 patients, and that the ORF8 protein could be a novel therapeutic target in severe COVID-19 patients.