Cytomegalovirus subverts macrophage identity

Cell. 2021 Jul 8;184(14):3774-3793.e25. doi: 10.1016/j.cell.2021.05.009. Epub 2021 Jun 10.


Cytomegaloviruses (CMVs) have co-evolved with their mammalian hosts for millions of years, leading to remarkable host specificity and high infection prevalence. Macrophages, which already populate barrier tissues in the embryo, are the predominant immune cells at potential CMV entry sites. Here we show that, upon CMV infection, macrophages undergo a morphological, immunophenotypic, and metabolic transformation process with features of stemness, altered migration, enhanced invasiveness, and provision of the cell cycle machinery for viral proliferation. This complex process depends on Wnt signaling and the transcription factor ZEB1. In pulmonary infection, mouse CMV primarily targets and reprograms alveolar macrophages, which alters lung physiology and facilitates primary CMV and secondary bacterial infection by attenuating the inflammatory response. Thus, CMV profoundly perturbs macrophage identity beyond established limits of plasticity and rewires specific differentiation processes, allowing viral spread and impairing innate tissue immunity.

Keywords: CMV; EMT; Legionella pneumophila; alveolar macrophage; co-evolution; cytomegalovirus; epithelial-mesenchymal transition; host-pathogen interaction; macrophage; myeloid cell differentiation; respiratory tract infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • Bystander Effect
  • Cell Cycle
  • Cell Line, Transformed
  • Cellular Reprogramming
  • Cytomegalovirus / pathogenicity
  • Cytomegalovirus / physiology*
  • Cytomegalovirus / ultrastructure
  • Cytomegalovirus Infections / immunology
  • Cytomegalovirus Infections / virology
  • Green Fluorescent Proteins / metabolism
  • Lung / pathology
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / ultrastructure
  • Macrophages, Alveolar / virology*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phenotype
  • Stem Cells / pathology
  • Virus Replication / physiology
  • Wnt Signaling Pathway


  • Green Fluorescent Proteins