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- W4313430151 abstract "Abstract Angiotensin-converting enzyme 2 (ACE2) receptor is required for SARS-CoV-2 entry into human cells. However, emerging evidence shows SARS-CoV-2 infected lung monocytes/macrophages from COVID-19 patients barely express ACE2 mRNA, raising a question how SARS-CoV-2 penetrates macrophages. It’s also under debating whether the peripheral blood cells (HPBCs) can be infected by SARS-CoV-2 that may facilitate viral spread from circulation to other organs besides lung. Herein we demonstrate that resting primary HPBCs harbor abundant cytoplasmic ACE2, regardless of COVID-19 status, and that surface translocation is necessary for viral infection. Upon ex vivo TLR4/7/8 stimulation of HPBCs, ACE2 translocated to the cell surface independent of ACE2 transcription, and this translocation was blocked by an endosomal trafficking inhibitor, suggesting the putative source as ACE2-containing exosomes. However, only stimulated monocytes concurrently expressing ACE2 and cell surface transmembrane serine protease type 2 (TMPRSS2) were efficiently infected by SARS-CoV-2, which was significantly mitigated by remdesivir. Furthermore, ACE2 surface translocation in peripheral myeloid cells from patients with severe COVID-19 correlated with their proinflammatory cytokine production. Collectively, TLR4/7/8-induced ACE2 translocation with TMPRSS2 expression is indispensable for SARS-CoV-2 infection of circulating monocytes. Our work not only provides a new mechanism for the pathogenesis of SARS-CoV-2 and a potential path for its systemic infection, but also unveils a prospective therapeutic strategy by targeting ACE2 trafficking for preventing monocyte/macrophage infection. This study is partially supported by National Institutes of Health grants R61AR076803, R01AR063611, R01AI119041, and R01AR069681 (Q-S. M.), R01AR072046 (L.Z.), R01DK120623 (J.Z.S.), Henry Ford Immunology Program grants (T71016, Q-S. M.; T71017, L. Z.), and funding for the U-M Center for Drug Repurposing - NCATS CTSA UL1TR002240 (J.Z.S.)." @default.
- W4313430151 created "2023-01-06" @default.
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- W4313430151 date "2022-05-01" @default.
- W4313430151 modified "2023-09-26" @default.
- W4313430151 title "Circulating Monocytes Co-expressing Surface ACE2 and TMPRSS2 upon TLR4/7/8 Activation Are Susceptible to SARS-CoV-2 Infection" @default.
- W4313430151 doi "https://doi.org/10.4049/jimmunol.208.supp.163.25" @default.
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