2. Academic Validation
  3. Surface translocation of ACE2 and TMPRSS2 upon TLR4/7/8 activation is required for SARS-CoV-2 infection in circulating monocytes

Surface translocation of ACE2 and TMPRSS2 upon TLR4/7/8 activation is required for SARS-CoV-2 infection in circulating monocytes

  • Cell Discov. 2022 Sep 9;8(1):89. doi: 10.1038/s41421-022-00453-8.
Yi Yao  # 1 2,  Kalpana Subedi  # 1 2,  Tingting Liu 1 2,  Namir Khalasawi 1 2,  Carla Diana Pretto-Kernahan 3 4,  Jesse William Wotring 3 5,  Jie Wang 1 2,  Congcong Yin 1 2,  Aimin Jiang 1 2,  Chunmei Fu 1 2,  Peter Dimitrion 1 2 6,  Jia Li 7,  Jesse Veenstra 1 2,  Qijun Yi 1 2,  Kathy McKinnon 8,  John Ernest McKinnon 9,  Jonathan Zachary Sexton 10 11 12,  Li Zhou 13 14 15 16,  Qing-Sheng Mi 17 18 19 20
Affiliations

Affiliations

  • 1 Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health System, Detroit, MI, USA.
  • 2 Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, USA.
  • 3 Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
  • 4 University of Michigan Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, USA.
  • 5 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
  • 6 Department of Biochemistry, Microbiology, and Immunology, School of Medicine, Wayne State University, Detroit, MI, USA.
  • 7 Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.
  • 8 Division of Rheumatology, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
  • 9 Division of Infectious Diseases, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
  • 10 Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 11 University of Michigan Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 12 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 13 Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health System, Detroit, MI, USA. [email protected].
  • 14 Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, USA. [email protected].
  • 15 Department of Biochemistry, Microbiology, and Immunology, School of Medicine, Wayne State University, Detroit, MI, USA. [email protected].
  • 16 Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA. [email protected].
  • 17 Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health System, Detroit, MI, USA. [email protected].
  • 18 Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, USA. [email protected].
  • 19 Department of Biochemistry, Microbiology, and Immunology, School of Medicine, Wayne State University, Detroit, MI, USA. [email protected].
  • 20 Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA. [email protected].
  • # Contributed equally.
PMID: 36085197 DOI: 10.1038/s41421-022-00453-8
Abstract

Infection of human peripheral blood cells by SARS-CoV-2 has been debated because immune cells lack mRNA expression of both angiotensin-converting Enzyme 2 (ACE2) and transmembrane serine protease type 2 (TMPRSS2). Herein we demonstrate that resting primary monocytes harbor abundant cytoplasmic ACE2 and TMPRSS2 protein and that circulating exosomes contain significant ACE2 protein. Upon ex vivo TLR4/7/8 stimulation, cytoplasmic ACE2 was quickly translocated to the monocyte cell surface independently of ACE2 transcription, while TMPRSS2 surface translocation occurred in conjunction with elevated mRNA expression. The rapid translocation of ACE2 to the monocyte cell surface was blocked by the endosomal trafficking inhibitor endosidin 2, suggesting that endosomal ACE2 could be derived from circulating ACE2-containing exosomes. TLR-stimulated monocytes concurrently expressing ACE2 and TMPRSS2 on the cell surface were efficiently infected by SARS-CoV-2, which was significantly mitigated by remdesivir, TMPRSS2 inhibitor camostat, and anti-ACE2 antibody. Mass cytometry showed that ACE2 surface translocation in peripheral myeloid cells from patients with severe COVID-19 correlated with its hyperactivation and PD-L1 expression. Collectively, TLR4/7/8-induced ACE2 translocation with TMPRSS2 expression makes circulating monocytes permissive to SARS-CoV-2 Infection.

Figures
Products