ACE2-independent infection of T lymphocytes by SARS-CoV-2

• Published in: Signal transduction and targeted therapy Vol. 7; no. 1; pp. 83 - 11
• Main Authors: Shen, Xu-Rui, Geng, Rong, Li, Qian, Chen, Ying, Li, Shu-Fen, Wang, Qi, Min, Juan, Yang, Yong, Li, Bei, Jiang, Ren-Di, Wang, Xi, Zheng, Xiao-Shuang, Zhu, Yan, Jia, Jing-Kun, Yang, Xing-Lou, Liu, Mei-Qin, Gong, Qian-Chun, Zhang, Yu-Lan, Guan, Zhen-Qiong, Li, Hui-Ling, Zheng, Zhen-Hua, Shi, Zheng-Li, Zhang, Hui-Lan, Peng, Ke, Zhou, Peng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.03.2022; Nature Publishing Group
• Subjects: 631/250; 631/326; ACE2; Angiotensin-converting enzyme 2; Antigens; Apoptosis; Autopsy; Cancer Research; CD4 antigen; Cell Biology; Cell death; Coronaviruses; COVID-19; Hypoxia-inducible factor 1a; Infections; Internal Medicine; Leukocytes; LFA-1 antigen; Lymphocytes; Lymphocytes T; Lymphopenia; Medicine; Medicine & Public Health; Mitochondria; Oncology; Pathology; Patients; Peripheral blood; Ribonucleic acid; RNA; Severe acute respiratory syndrome coronavirus 2; Viral infections
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-022-00919-x

SARS-CoV-2 induced marked lymphopenia in severe patients with COVID-19. However, whether lymphocytes are targets of viral infection is yet to be determined, although SARS-CoV-2 RNA or antigen has been identified in T cells from patients. Here, we confirmed that SARS-CoV-2 viral antigen could be detected in patient peripheral blood cells (PBCs) or postmortem lung T cells, and the infectious virus could also be detected from viral antigen-positive PBCs. We next prove that SARS-CoV-2 infects T lymphocytes, preferably activated CD4 + T cells in vitro. Upon infection, viral RNA, subgenomic RNA, viral protein or viral particle can be detected in the T cells. Furthermore, we show that the infection is spike-ACE2/TMPRSS2-independent through using ACE2 knockdown or receptor blocking experiments. Next, we demonstrate that viral antigen-positive T cells from patient undergone pronounced apoptosis. In vitro infection of T cells induced cell death that is likely in mitochondria ROS-HIF-1a-dependent pathways. Finally, we demonstrated that LFA-1, the protein exclusively expresses in multiple leukocytes, is more likely the entry molecule that mediated SARS-CoV-2 infection in T cells, compared to a list of other known receptors. Collectively, this work confirmed a SARS-CoV-2 infection of T cells, in a spike-ACE2-independent manner, which shed novel insights into the underlying mechanisms of SARS-CoV-2-induced lymphopenia in COVID-19 patients.