Hyun-Woo Jeong1,10, Jeong Seok Lee2,10, Jae-Hoon Ko3,10, Seunghee Hong4, Sang Taek Oh5, Seongkyun Choi5, Kyong Ran Peck3, Ji Hun Yang5, Seok Chung5,6, Sung-Han Kim7, Yeon-Sook Kim8 and Eui-Cheol Shin2,9
1Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster 48149, Germany.
2Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
3Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
4Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
5School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea.
6KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
7Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
8Division of Infectious Diseases, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea.
9The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea.
10These authors contributed equally: Hyun-Woo Jeong, Jeong Seok Lee, Jae-Hoon Ko.
Corresponding authors : Correspondence to Kyong Ran Peck, Ji Hun Yang, Seok Chung, Sung-Han Kim, Yeon-Sook Kim or Eui-Cheol Shin.
We do not yet understand exactly how corticosteroids attenuate hyperinflammatory responses and alleviate high-risk coronavirus disease 2019 (COVID-19). We aimed to reveal the molecular mechanisms of hyperinflammation in COVID-19 and the antiinflammatory effects of corticosteroids in patients with high-risk COVID-19. We performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from three independent COVID-19 cohorts: cohort 1 was used for comparative analysis of highrisk and low-risk COVID-19 (47 PBMC samples from 28 patients), cohort 2 for longitudinal analysis during COVID-19 (57 PBMC samples from 15 patients), and cohort 3 for investigating the effects of corticosteroid treatment in patients with high-risk COVID-19(55 PBMC samples from 13 patients). PBMC samples from healthy donors (12 PBMC samples from 12 donors) were also included. Cohort 1 revealed a significant increase in the proportion of monocytes expressing the long noncoding RNAs NEAT1 and MALAT1 in high-risk patients. Cohort 2 showed that genes encoding inflammatory chemokines and their receptors were upregulated during aggravation, whereas genes related to angiogenesis were upregulated during improvement. Cohort 3 demonstrated downregulation of interferon-stimulated genes (ISGs), including STAT1, in monocytes after corticosteroid treatment. In particular, unphosphorylated STAT-dependent ISGs enriched in monocytes from lupus patients were selectively downregulated by corticosteroid treatment in patients with high-risk COVID-19. Corticosteroid treatment suppresses pathologic interferon responses in monocytes by downregulating STAT1 in patients with high-risk COVID-19. Our study provides insights into the mechanisms underlying COVID-19 aggravation and improvement and the effects of corticosteroid treatment.