Intracranial calcifications in congenital viral infections: mechanisms and cellular roles

Abstract

Intracranial calcifications (ICCs) are a characteristic neuropathological feature of several congenital viral infections, including Zika virus (ZIKV), cytomegalovirus (CMV), and lymphocytic choriomeningitis virus (LCMV). These lesions are linked to severe neurodevelopmental outcomes, such as microcephaly, epilepsy, and cognitive deficits, yet the mechanisms underlying their formation and resolution remain unclear. ICCs are thought to arise from an imbalance in osteogenic and osteolytic signaling in the developing brain. Recent work implicates pericytes as key targets of ZIKV, capable of osteogenic reprogramming and direct mineral deposition. However, the pathways leading to calcification in CMV and LCMV infections are less well understood. Microglia, the brain’s resident immune cells, have emerged as potential regulators of calcification. While microglia can limit mineral deposition in noninfectious models of neurodegeneration and injury, their role in the context of congenital viral infection remains speculative. Whether they act to contain calcification, participate in its resolution, or contribute to pathogenesis via neuroinflammatory signaling is still unknown. This short review summarizes current knowledge of ICC pathogenesis during congenital ZIKV, CMV, and LCMV infections, with a focus on emerging potential cellular mediators, such as pericytes and microglia. We discuss known mechanisms, gaps in knowledge, and opportunities to build more representative animal models to elucidate how different viral infections orchestrate calcification in the fetal brain. Clarifying these pathways may inform future therapeutic approaches to mitigate virus-induced neurodevelopmental disorders.