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ACE2-independent SARS-CoV-2 virus entry through cell surface GRP78 on monocytes - evidence from a translational clinical and experimental approach.
EBioMedicine 98:104869 (2023)
BACKGROUND: SARS-CoV-2 infects host cells via an ACE2/TMPRSS2 entry mechanism. Monocytes and macrophages, which play a key role during severe COVID-19 express only low or no ACE2, suggesting alternative entry mechanisms in these cells. In silico analyses predicted GRP78, which is constitutively expressed on monocytes and macrophages, to be a potential candidate receptor for SARS-CoV-2 virus entry. METHODS: Hospitalized COVID-19 patients were characterized regarding their pro-inflammatory state and cell surface GRP78 (csGRP78) expression in comparison to healthy controls. RNA from CD14+ monocytes of patients and controls were subjected to transcriptome analysis that was specifically complemented by bioinformatic re-analyses of bronchoalveolar lavage fluid (BALF) datasets of COVID-19 patients with a focus on monocyte/macrophage subsets, SARS-CoV-2 infection state as well as GRP78 gene expression. Monocyte and macrophage immunohistocytochemistry on GRP78 was conducted in post-mortem lung tissues. SARS-CoV-2 spike and GRP78 protein interaction was analyzed by surface plasmon resonance, GST Pull-down and Co-Immunoprecipitation. SARS-CoV-2 pseudovirus or single spike protein uptake was quantified in csGRP78high THP-1 cells. FINDINGS: Cytokine patterns, monocyte activation markers and transcriptomic changes indicated typical COVID-19 associated inflammation accompanied by upregulated csGRP78 expression on peripheral blood and lung monocytes/macrophages. Subsequent cell culture experiments confirmed an association between elevated pro-inflammatory cytokine levels and upregulation of csGRP78. Interaction of csGRP78 and SARS-CoV-2 spike protein with a dissociation constant of KD = 55.2 nM was validated in vitro. Infection rate analyses in ACE2low and GRP78high THP-1 cells showed increased uptake of pseudovirus expressing SARS-CoV-2 spike protein. INTERPRETATION: Our results demonstrate that csGRP78 acts as a receptor for SARS-CoV-2 spike protein to mediate ACE2-independent virus entry into monocytes. FUNDING: Funded by the Sino-German-Center for Science Promotion (C-0040) and the Germany Ministry BMWi/K [DLR-grant 50WB1931 and RP1920 to AC, DM, TW].
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cell Stress ; Grp78 ; Monocytes ; Sars-cov-2 ; Thp-1 cells ; Viral Entry; Glucose-regulated Protein; Receptor; Bip; Macrophages
Language
english
Publication Year
2023
HGF-reported in Year
2023
ISSN (print) / ISBN
2352-3964
e-ISSN
2352-3964
Journal
EBioMedicine
Quellenangaben
Volume: 98,
Article Number: 104869
Publisher
Elsevier
Publishing Place
Amsterdam [u.a.]
Reviewing status
Peer reviewed
Institute(s)
Institute of Lung Health and Immunity (LHI)
POF-Topic(s)
30202 - Environmental Health
Research field(s)
Lung Research
PSP Element(s)
G-505000-001
Grants
Germany Ministry BMWi/K
Sino-German-Center for Science Promotion
Sino-German-Center for Science Promotion
WOS ID
001113740900001
Scopus ID
85176468281
PubMed ID
37967509
Erfassungsdatum
2023-11-28