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.
Keywords: immune regulation SARS-CoV-2 ORF8, viral cytokine
Graphical Abstract
Graphical Abstract.
Contributor Information
Masako Kohyama, Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan; Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan.
Tatsuya Suzuki, Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan; Center for Infectious Diseases Education and Research, Osaka University, Osaka, 565-0871, Japan.
Wataru Nakai, Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan; Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan.
Chikako Ono, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.
Sumiko Matsuoka, Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan; Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan.
Koichi Iwatani, Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan; Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan.
Yafei Liu, Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan; Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan.
Yusuke Sakai, Department of Veterinary Pathology, Yamaguchi University, Yamaguchi, Japan.
Atsushi Nakagawa, Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Hyogo, 650-0047, Japan.
Keisuke Tomii, Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Hyogo, 650-0047, Japan.
Koichiro Ohmura, Department of Rheumatology, Kobe City Medical Center General Hospital, Hyogo, 650-0047, Japan.
Masato Okada, Center for Infectious Diseases Education and Research, Osaka University, Osaka, 565-0871, Japan; Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.
Yoshiharu Matsuura, Center for Infectious Diseases Education and Research, Osaka University, Osaka, 565-0871, Japan; Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.
Shiro Ohshima, Department of Clinical Research, Osaka Minami Medical Center, Osaka, 586-8521, Japan.
Yusuke Maeda, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.
Toru Okamoto, Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan; Center for Infectious Diseases Education and Research, Osaka University, Osaka, 565-0871, Japan.
Hisashi Arase, Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan; Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan; Center for Infectious Diseases Education and Research, Osaka University, Osaka, 565-0871, Japan.
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