Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model PMID: 35440562

ADC Targets in Oncology

2026-04-10

Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model

Nat Commun. 2022 Apr 19;13(1):2028. doi: 10.1038/s41467-022-29731-5.

Qizhou Lian ^# ¹ ² , Kui Zhang ^# ³ ⁴ , Zhao Zhang ^# ⁵ , Fuyu Duan ^# ⁶ , Liyan Guo ^# ⁶ , Weiren Luo ⁷ , Bobo Wing-Yee Mok ⁸ , Abhimanyu Thakur ³ ⁴ , Xiaoshan Ke ³ ⁴ , Pedram Motallebnejad ³ ⁴ , Vlad Nicolaescu ⁹ , Jonathan Chen ¹⁰ , Chui Yan Ma ⁶ , Xiaoya Zhou ⁵ , Shuo Han ¹¹ , Teng Han ¹² , Wei Zhang ¹³ , Adrian Y Tan ¹³ , Tuo Zhang ¹³ , Xing Wang ¹³ , Dong Xu ¹³ , Jenny Xiang ¹³ , Aimin Xu ¹⁴ , Can Liao ⁶ , Fang-Ping Huang ¹⁵ , Ya-Wen Chen ¹⁶ ¹⁷ , Jie Na ¹⁸ , Glenn Randall ⁹ , Hung-Fat Tse ⁵ , Zhiwei Chen ¹⁹ , Yin Chen ²⁰ , Huanhuan Joyce Chen ²¹ ²²

Affiliations

1. Cord Blood Bank Center, Cord Blood Bank, Guangzhou Institute of Eugenics and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. [email protected].
2. HKUMed Laboratory of Cellular Therapeutics, and Department of Medicine, the University of Hong Kong, Hong Kong SAR, China. [email protected].
3. The Pritzker School of Molecular Engineering, the University of Chicago, Chicago, IL, 60637, USA.
4. The Ben May Department for Cancer Research, the University of Chicago, Chicago, IL, 60637, USA.
5. HKUMed Laboratory of Cellular Therapeutics, and Department of Medicine, the University of Hong Kong, Hong Kong SAR, China.
6. Cord Blood Bank Center, Cord Blood Bank, Guangzhou Institute of Eugenics and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
7. Department of Pathology, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen Third People's Hospital, National Clinical Research Centre for Infectious Diseases, Shenzhen, China.
8. Department of Microbiology and State Key Laboratory for Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
9. Microbiology, Biosciences Division, the University of Chicago, Chicago, IL, 60637, USA.
10. McCormick School of Engineering, Northwestern University, Chicago, IL, USA.
11. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
12. Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10021, USA.
13. Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY, 10065, USA.
14. State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
15. Institute for Advanced Study (IAS), Shenzhen University, Shenzhen, China.
16. Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
17. Department of Cell, Developmental, and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
18. School of Medicine, Tsinghua University, Beijing, China.
19. AIDS Institute and Department of Microbiology, State Key Laboratory of Emergent Infectious Disease, The University of Hong Kong, Hong Kong, China.
20. Department of Pharmacology and Toxicology, School of Pharmacy, University of Arizona, Tucson, AZ, USA.
21. The Pritzker School of Molecular Engineering, the University of Chicago, Chicago, IL, 60637, USA. [email protected].
22. The Ben May Department for Cancer Research, the University of Chicago, Chicago, IL, 60637, USA. [email protected].
# Contributed equally.

Abstract

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19), with macrophages as one of the main cell types involved. It is urgent to understand the interactions among permissive cells, macrophages, and the SARS-CoV-2 virus, thereby offering important insights into effective therapeutic strategies. Here, we establish a lung and macrophage co-culture system derived from human pluripotent stem cells (hPSCs), modeling the host-pathogen interaction in SARS-CoV-2 Infection. We find that both classically polarized macrophages (M1) and alternatively polarized macrophages (M2) have inhibitory effects on SARS-CoV-2 Infection. However, M1 and non-activated (M0) macrophages, but not M2 macrophages, significantly up-regulate inflammatory factors upon viral Infection. Moreover, M1 macrophages suppress the growth and enhance Apoptosis of lung cells. Inhibition of viral entry using an ACE2 blocking antibody substantially enhances the activity of M2 macrophages. Our studies indicate differential immune response patterns in distinct macrophage phenotypes, which could lead to a range of COVID-19 disease severity.