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SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation of angiotensin II receptor signaling in epithelial cells.
Patra, Tapas; Meyer, Keith; Geerling, Lizzie; Isbell, T Scott; Hoft, Daniel F; Brien, James; Pinto, Amelia K; Ray, Ratna B; Ray, Ranjit.
  • Patra T; Department of Internal Medicine, Saint Louis University, Missouri, United States of America.
  • Meyer K; Department of Internal Medicine, Saint Louis University, Missouri, United States of America.
  • Geerling L; Department of Molecular Microbiology & Immunology, Saint Louis University, Missouri, United States of America.
  • Isbell TS; Department of Pathology, Saint Louis University, Missouri, United States of America.
  • Hoft DF; Department of Internal Medicine, Saint Louis University, Missouri, United States of America.
  • Brien J; Department of Molecular Microbiology & Immunology, Saint Louis University, Missouri, United States of America.
  • Pinto AK; Department of Molecular Microbiology & Immunology, Saint Louis University, Missouri, United States of America.
  • Ray RB; Department of Molecular Microbiology & Immunology, Saint Louis University, Missouri, United States of America.
  • Ray R; Department of Pathology, Saint Louis University, Missouri, United States of America.
PLoS Pathog ; 16(12): e1009128, 2020 12.
Article in English | MEDLINE | ID: covidwho-992722
Semantic information from SemMedBD (by NLM)
1. spike protei AUGMENTS C0558141
Subject
spike protei
Predicate
AUGMENTS
Object
C0558141
2. angiotensin-activated signaling pathway PROCESS_OF Epithelial Cells
Subject
angiotensin-activated signaling pathway
Predicate
PROCESS_OF
Object
Epithelial Cells
3. receptor expression PROCESS_OF angiotensin converting enzyme 2
Subject
receptor expression
Predicate
PROCESS_OF
Object
angiotensin converting enzyme 2
4. M Protei DISRUPTS C0597360
Subject
M Protei
Predicate
DISRUPTS
Object
C0597360
5. M Protei STIMULATES C0529330
Subject
M Protei
Predicate
STIMULATES
Object
C0529330
6. Serum PART_OF Patients
Subject
Serum
Predicate
PART_OF
Object
Patients
7. Soluble Interleukin-6 Receptor Subunit Alph PART_OF C0521119
Subject
Soluble Interleukin-6 Receptor Subunit Alph
Predicate
PART_OF
Object
C0521119
8. Soluble Interleukin-6 Receptor Subunit Alph STIMULATES C0030940
Subject
Soluble Interleukin-6 Receptor Subunit Alph
Predicate
STIMULATES
Object
C0030940
9. STAT3 gene|STAT3 INTERACTS_WITH SOCS3 gene|SOCS3
Subject
STAT3 gene|STAT3
Predicate
INTERACTS_WITH
Object
SOCS3 gene|SOCS3
10. STAT3 gene|STAT3 INTERACTS_WITH CCL2 protei
Subject
STAT3 gene|STAT3
Predicate
INTERACTS_WITH
Object
CCL2 protei
11. Viral Proteins INTERACTS_WITH Epithelial Cells
Subject
Viral Proteins
Predicate
INTERACTS_WITH
Object
Epithelial Cells
12. Human Cell Line PART_OF Endothelium
Subject
Human Cell Line
Predicate
PART_OF
Object
Endothelium
13. integral to membrane LOCATION_OF interleukin-6 receptor activity
Subject
integral to membrane
Predicate
LOCATION_OF
Object
interleukin-6 receptor activity
14. Human Cell Line LOCATION_OF 2019 novel coronavirus
Subject
Human Cell Line
Predicate
LOCATION_OF
Object
2019 novel coronavirus
15. interleukin-6 receptor activity CAUSES Phosphorylation
Subject
interleukin-6 receptor activity
Predicate
CAUSES
Object
Phosphorylation
16. Present PREDISPOSES Transsexual (finding)
Subject
Present
Predicate
PREDISPOSES
Object
Transsexual (finding)
17. Epithelial Cells LOCATION_OF spike protei
Subject
Epithelial Cells
Predicate
LOCATION_OF
Object
spike protei
18. spike protein, SARS-CoV-2 AUGMENTS Transsexual (finding)
Subject
spike protein, SARS-CoV-2
Predicate
AUGMENTS
Object
Transsexual (finding)
19. angiotensin-activated signaling pathway PROCESS_OF Epithelial Cells
Subject
angiotensin-activated signaling pathway
Predicate
PROCESS_OF
Object
Epithelial Cells
20. receptor expression PROCESS_OF angiotensin converting enzyme 2
Subject
receptor expression
Predicate
PROCESS_OF
Object
angiotensin converting enzyme 2
21. M Protein, multiple myeloma DISRUPTS receptor expression
Subject
M Protein, multiple myeloma
Predicate
DISRUPTS
Object
receptor expression
22. M Protein, multiple myeloma STIMULATES Receptor, Angiotensin, Type 1
Subject
M Protein, multiple myeloma
Predicate
STIMULATES
Object
Receptor, Angiotensin, Type 1
23. Serum PART_OF Patients
Subject
Serum
Predicate
PART_OF
Object
Patients
24. Soluble Interleukin-6 Receptor Subunit Alpha, Human PART_OF Extracellular
Subject
Soluble Interleukin-6 Receptor Subunit Alpha, Human
Predicate
PART_OF
Object
Extracellular
25. Soluble Interleukin-6 Receptor Subunit Alpha, Human STIMULATES Peptide Hydrolases
Subject
Soluble Interleukin-6 Receptor Subunit Alpha, Human
Predicate
STIMULATES
Object
Peptide Hydrolases
26. STAT3 gene|STAT3 INTERACTS_WITH SOCS3 gene|SOCS3
Subject
STAT3 gene|STAT3
Predicate
INTERACTS_WITH
Object
SOCS3 gene|SOCS3
27. STAT3 gene|STAT3 INTERACTS_WITH CCL2 protein, human|CCL2
Subject
STAT3 gene|STAT3
Predicate
INTERACTS_WITH
Object
CCL2 protein, human|CCL2
28. Viral Proteins INTERACTS_WITH Epithelial Cells
Subject
Viral Proteins
Predicate
INTERACTS_WITH
Object
Epithelial Cells
29. Human Cell Line PART_OF Endothelium
Subject
Human Cell Line
Predicate
PART_OF
Object
Endothelium
30. integral to membrane LOCATION_OF interleukin-6 receptor activity
Subject
integral to membrane
Predicate
LOCATION_OF
Object
interleukin-6 receptor activity
31. Human Cell Line LOCATION_OF 2019 novel coronavirus
Subject
Human Cell Line
Predicate
LOCATION_OF
Object
2019 novel coronavirus
32. interleukin-6 receptor activity CAUSES Phosphorylation
Subject
interleukin-6 receptor activity
Predicate
CAUSES
Object
Phosphorylation
33. Present PREDISPOSES Transsexual (finding)
Subject
Present
Predicate
PREDISPOSES
Object
Transsexual (finding)
34. Epithelial Cells LOCATION_OF spike protein, SARS-CoV-2
Subject
Epithelial Cells
Predicate
LOCATION_OF
Object
spike protein, SARS-CoV-2
ABSTRACT
Cytokine storm is suggested as one of the major pathological characteristics of SARS-CoV-2 infection, although the mechanism for initiation of a hyper-inflammatory response, and multi-organ damage from viral infection is poorly understood. In this virus-cell interaction study, we observed that SARS-CoV-2 infection or viral spike protein expression alone inhibited angiotensin converting enzyme-2 (ACE2) receptor protein expression. The spike protein promoted an angiotensin II type 1 receptor (AT1) mediated signaling cascade, induced the transcriptional regulatory molecules NF-κB and AP-1/c-Fos via MAPK activation, and increased IL-6 release. SARS-CoV-2 infected patient sera contained elevated levels of IL-6 and soluble IL-6R. Up-regulated AT1 receptor signaling also influenced the release of extracellular soluble IL-6R by the induction of the ADAM-17 protease. Use of the AT1 receptor antagonist, Candesartan cilexetil, resulted in down-regulation of IL-6/soluble IL-6R release in spike expressing cells. Phosphorylation of STAT3 at the Tyr705 residue plays an important role as a transcriptional inducer for SOCS3 and MCP-1 expression. Further study indicated that inhibition of STAT3 Tyr705 phosphorylation in SARS-CoV-2 infected and viral spike protein expressing epithelial cells did not induce SOCS3 and MCP-1 expression. Introduction of culture supernatant from SARS-CoV-2 spike expressing cells on a model human liver endothelial Cell line (TMNK-1), where transmembrane IL-6R is poorly expressed, resulted in the induction of STAT3 Tyr705 phosphorylation as well as MCP-1 expression. In conclusion, our results indicated that the presence of SARS-CoV-2 spike protein in epithelial cells promotes IL-6 trans-signaling by activation of the AT1 axis to initiate coordination of a hyper-inflammatory response.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Receptors, Angiotensin / Interleukin-6 / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: PLoS Pathog Year: 2020 Document Type: Article Affiliation country: Journal.ppat.1009128

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Receptors, Angiotensin / Interleukin-6 / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: PLoS Pathog Year: 2020 Document Type: Article Affiliation country: Journal.ppat.1009128