Decoding human cytomegalovirus for the development of innovative diagnostics to detect congenital infection

Abstract

Cytomegalovirus is the most common cause of congenital infectious disease and the leading nongenetic etiology of sensorineural hearing loss. Although most infected neonates are asymptomatic at birth, congenital cytomegalovirus infection is responsible for nearly 400 infant deaths annually in the United States and may lead to significant long-term neurodevelopmental impairments in survivors. The resulting financial and social burdens of congenital cytomegalovirus infection have led many medical centers to initiate targeted testing after birth, with a growing advocacy to advance universal newborn screening. While no cures or vaccines are currently available to eliminate or prevent cytomegalovirus infection, much has been learned over the last five years regarding disease pathophysiology and viral replication cycles that may enable the development of innovative diagnostics and therapeutics. This Review will detail our current understanding of congenital cytomegalovirus infection, while focusing our discussion on routine and emerging diagnostics for viral detection, quantification, and long-term prognostication. IMPACT: This review highlights our current understanding of the fetal transmission of human cytomegalovirus. It details clinical signs and physical findings of congenital cytomegalovirus infection. This submission discusses currently available cytomegalovirus diagnostics and introduces emerging platforms that promise improved sensitivity, specificity, limit of detection, viral quantification, detection of genomic antiviral resistance, and infection staging (primary, latency, reactivation, reinfection).

Fig. 1. Pathophysiology of congenital cytomegalovirus infection.

(Right, Maternal Infection) Maternal lytic infection is caused by primary infection, reactivation of latent infection, or reinfection with a new strain (i.e., superinfection). The inner cytotrophoblast is surrounded by placental fibroblasts and macrophages that directly contact the developing fetal blood vessels, while the outer syncytiotrophoblast layer is thought to be human cytomegalovirus (CMV) permissive.^, Once in the fetal bloodstream, the virus can spread to susceptible cell types, including fetal endothelial cells, fibroblasts, and smooth muscle cells, mainly through cell-to-cell transmission but also by cell-free mechanisms.^, (Middle, Fetal Infection) HCMV develops life-long infection due to its ability to establish latency in peripheral blood monocytes and CD34⁺ hematopoietic stem and progenitor cells (HSPCs).^, Subsequent entry of infected monocytes into tissues causes their differentiation into either macrophages or dendritic cells, which drives viral reactivation and propagation.^– (Left, Neonatal Findings) Clinical signs of congenital cytomegalovirus (cCMV) infection included small for gestational age (SGA), intrauterine growth restriction (IUGR), preterm birth, microcephaly, congenital hydrocephalus, chorioretinitis, thrombocytopenia, anemia, hypertransaminemia, hepatomegaly, and sensorineural hearing loss (SNHL).^,