Breaking barriers: how cytomegaloviruses manipulate myeloid cells to invade tissues

Cytomegaloviruses are highly adapted to their hosts through millions of years of co-evolution. Most human (H)CMV infections occur early in life when the virus enters via the mucosal surfaces of the respiratory or gastrointestinal tract. These infections are usually asymptomatic, but coincide with critical phases of immune development, shaping long-term host immunity. In rare but clinically significant cases, CMV can invade protected sites, such as the central nervous system, leading to symptomatic disease. As the most abundant immune cells at barrier sites, myeloid cells support all stages of the viral life cycle: replication, dissemination, and latency. During the perinatal period, the myeloid compartment undergoes profound changes, including macrophage maturation, monocyte influx, and functional adaptation. CMV may exploit these developmental transitions to establish infection and to cross tissue barriers. This review discusses how CMV manipulates myeloid immune cells to establish postnatal infection, particularly via the respiratory tract, and explores strategies by which CMVs breach the placental barrier and access the fetal brain. The review integrates evidence from multiple CMV species, with emphasis on human and mouse data.