Cytomegalovirus subverts macrophage identity

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Cytomegaloviruses (CMVs) exhibit high host specificity and prevalence due to long-term co-evolution with mammalian hosts.
• Macrophages are key immune cells at barrier tissues, crucial for initial defense against pathogens like CMV.

Purpose of the Study:

• To investigate the impact of CMV infection on macrophage identity and function.
• To elucidate the mechanisms by which CMV manipulates macrophages for viral proliferation and spread.

Main Methods:

• Analysis of macrophage transformation upon CMV infection, including morphological, immunophenotypic, and metabolic changes.
• Investigation of the roles of Wnt signaling and the transcription factor ZEB1 in CMV-induced macrophage reprogramming.
• Assessment of the consequences of reprogrammed alveolar macrophages in a pulmonary mouse CMV infection model.

Main Results:

• CMV infection induces macrophages to acquire stemness features, altering migration, invasiveness, and cell cycle regulation.
• Wnt signaling and ZEB1 are critical for this complex macrophage transformation process.
• In pulmonary infections, mouse CMV reprograms alveolar macrophages, dampening inflammatory responses and enabling secondary bacterial infections.

Conclusions:

• CMV profoundly alters macrophage identity, exceeding typical cellular plasticity limits.
• The virus rewires macrophage differentiation pathways to enhance viral spread and compromise innate tissue immunity.