4.8 Article

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

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29731-5

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资金

  1. U.S. National Institute of Health [NCI R00 CA226353-01A1, NCI K99 CA226353-01A1]
  2. Cancer Research Foundation Young Investigator Award
  3. Janet D. Rowley Discovery Fund
  4. Hong Kong Health and Medical Research Fund (HMRF), Hong Kong [06172956]
  5. Start-up Grant for Stem Cell Regenerative Medicine (Guangzhou Women and Children's Medical Centre) [5001-4001010]
  6. Shenzhen Science and Technology Program [JCYJ20210324114606019]
  7. Tsinghua University Spring Breeze Fund [2021Z99CFY033]
  8. National Key R&D Program of China [2019YFA0110001, 2017YFA0102802]
  9. National Natural Science Grant of China [31970819]

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This study uses a lung and macrophage co-culture system derived from human pluripotent stem cells to investigate the phenotype and gene expression changes in host lung cells and macrophages after SARS-CoV-2 infection. The researchers found differential immune response patterns in distinct macrophage phenotypes, which could contribute to the severity of COVID-19 disease.
Model systems to study SARS-CoV-2 infection are required to better understand the immune response. Here the authors use a lung and macrophage co-culture system by differentiation of human pluripotent stem cells to better understand the phenotype and gene expression changes in host lung cells and macrophages after SARS-CoV-2 infection in vitro. 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.

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