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Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2.
Res Sq ; 2020 Aug 20.
Article in English | MEDLINE | ID: covidwho-729814
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
See preprint
Semantic information from SemMedBD (by NLM)
1. ACE2 gene|ACE2 DISRUPTS macrophage
Subject
ACE2 gene|ACE2
Predicate
DISRUPTS
Object
macrophage
2. Pluripotent Stem Cells PART_OF Homo sapiens
Subject
Pluripotent Stem Cells
Predicate
PART_OF
Object
Homo sapiens
3. Severe Acute Respiratory Syndrome CAUSES Host-Pathogen Interactions
Subject
Severe Acute Respiratory Syndrome
Predicate
CAUSES
Object
Host-Pathogen Interactions
4. ciliated cell PRODUCES TMPRSS2 gene|TMPRSS2
Subject
ciliated cell
Predicate
PRODUCES
Object
TMPRSS2 gene|TMPRSS2
5. ciliated cell PRODUCES ACE2 gene|ACE2
Subject
ciliated cell
Predicate
PRODUCES
Object
ACE2 gene|ACE2
6. interleukin-6 DISRUPTS Growth
Subject
interleukin-6
Predicate
DISRUPTS
Object
Growth
7. interleukin 18 protei DISRUPTS C0018270
Subject
interleukin 18 protei
Predicate
DISRUPTS
Object
C0018270
8. interleukin 18 protei DISRUPTS C0162638
Subject
interleukin 18 protei
Predicate
DISRUPTS
Object
C0162638
9. interleukin-6 DISRUPTS Apoptosis
Subject
interleukin-6
Predicate
DISRUPTS
Object
Apoptosis
10. Antibodie STIMULATES C4086555
Subject
Antibodie
Predicate
STIMULATES
Object
C4086555
11. Antibodie ADMINISTERED_TO C0221284
Subject
Antibodie
Predicate
ADMINISTERED_TO
Object
C0221284
12. M1 Macrophage INTERACTS_WITH Leptocyte
Subject
M1 Macrophage
Predicate
INTERACTS_WITH
Object
Leptocyte
13. M2 Macrophage INTERACTS_WITH macrophage
Subject
M2 Macrophage
Predicate
INTERACTS_WITH
Object
macrophage
14. ACE2 gene|ACE2 DISRUPTS macrophage
Subject
ACE2 gene|ACE2
Predicate
DISRUPTS
Object
macrophage
15. Pluripotent Stem Cells PART_OF Homo sapiens
Subject
Pluripotent Stem Cells
Predicate
PART_OF
Object
Homo sapiens
16. Severe Acute Respiratory Syndrome CAUSES Host-Pathogen Interactions
Subject
Severe Acute Respiratory Syndrome
Predicate
CAUSES
Object
Host-Pathogen Interactions
17. ciliated cell PRODUCES TMPRSS2 gene|TMPRSS2
Subject
ciliated cell
Predicate
PRODUCES
Object
TMPRSS2 gene|TMPRSS2
18. ciliated cell PRODUCES ACE2 gene|ACE2
Subject
ciliated cell
Predicate
PRODUCES
Object
ACE2 gene|ACE2
19. interleukin-6 DISRUPTS Growth
Subject
interleukin-6
Predicate
DISRUPTS
Object
Growth
20. interleukin 18 protein, human|IL18 DISRUPTS Growth
Subject
interleukin 18 protein, human|IL18
Predicate
DISRUPTS
Object
Growth
21. interleukin 18 protein, human|IL18 DISRUPTS Apoptosis
Subject
interleukin 18 protein, human|IL18
Predicate
DISRUPTS
Object
Apoptosis
22. interleukin-6 DISRUPTS Apoptosis
Subject
interleukin-6
Predicate
DISRUPTS
Object
Apoptosis
23. Antibodies, Blocking STIMULATES M2 Macrophage
Subject
Antibodies, Blocking
Predicate
STIMULATES
Object
M2 Macrophage
24. Antibodies, Blocking ADMINISTERED_TO Leptocyte
Subject
Antibodies, Blocking
Predicate
ADMINISTERED_TO
Object
Leptocyte
25. M1 Macrophage INTERACTS_WITH Leptocyte
Subject
M1 Macrophage
Predicate
INTERACTS_WITH
Object
Leptocyte
26. M2 Macrophage INTERACTS_WITH macrophage
Subject
M2 Macrophage
Predicate
INTERACTS_WITH
Object
macrophage
ABSTRACT
Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.

Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Year: 2020 Document Type: Article

Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Year: 2020 Document Type: Article