[Title]
Corticosteroids reduce pathologic interferon responses by downregulating STAT1 in patients with high-risk COVID-19

[Author] 
Hyun-Woo Jeong 1,10, 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 Shin 2,9

1 Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster 48149, Germany.
2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
3 Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
4 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
5 School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea.
6 KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
7 Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
8 Division of Infectious Diseases, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea.
9 The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea.
10 These authors contributed equally: Hyun-Woo Jeong, Jeong Seok Lee, Jae-Hoon Ko. 

[Journal] 
Experimental & Molecular Medicine volume 55, pages653–664 (2023)

[Abstract]
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 anti-inflammatory 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 high-risk 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.