SARS-CoV-2 Delta (B.1.617.2) variant replicates and induces syncytia formation in human induced pluripotent stem cell-derived macrophages

PeerJ. 2023 Mar 2:11:e14918. doi: 10.7717/peerj.14918. eCollection 2023.


Alveolar macrophages are tissue-resident immune cells that protect epithelial cells in the alveoli from invasion by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, the interaction between macrophages and SARS-CoV-2 is inevitable. However, little is known about the role of macrophages in SARS-CoV-2 infection. Here, we generated macrophages from human induced pluripotent stem cells (hiPSCs) to investigate the susceptibility of hiPSC-derived macrophages (iMΦ) to the authentic SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variants as well as their gene expression profiles of proinflammatory cytokines during infection. With undetectable angiotensin-converting enzyme 2 (ACE2) mRNA and protein expression, iMΦ were susceptible to productive infection with the Delta variant, whereas infection of iMΦ with the Omicron variant was abortive. Interestingly, Delta induced cell-cell fusion or syncytia formation in iMΦ, which was not observed in Omicron-infected cells. However, iMΦ expressed moderate levels of proinflammatory cytokine genes in response to SARS-CoV-2 infection, in contrast to strong upregulation of these cytokine genes in response to polarization by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). Overall, our findings indicate that the SARS-CoV-2 Delta variant can replicate and cause syncytia formation in macrophages, suggesting that the Delta variant can enter cells with undetectable ACE2 levels and exhibit greater fusogenicity.

Keywords: Cytokines; Human induced pluripotent stem cells; Macrophages; SARS-CoV-2; Syncytia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • COVID-19* / virology
  • Cytokines / genetics
  • Giant Cells*
  • Humans
  • Induced Pluripotent Stem Cells*
  • Macrophages
  • SARS-CoV-2 / genetics


  • Angiotensin-Converting Enzyme 2
  • Cytokines

Supplementary concepts

  • SARS-CoV-2 variants

Grants and funding

This work was supported by the National Center for Genetic Engineering and Biotechnology, Thailand (P-18-50193) to Thanathom Chailangkarn, and the National Science and Technology Development Agency, Thailand (P-22-51086) to Anan Jongkaewwattana. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.