Cytomegalovirus infection and pathogenesis in the human placenta
Lenore Pereira, Takako Tabata, Matthew Petitt
Human cytomegalovirus (HCMV) is the most common cause of congenital viral infection. Affected children can have permanent neurological complications, including hearing loss, visual impairment and mental retardation 1-3 . In Australia, 57% of women are seronegative and at risk for primary infection and transmission of virus to the fetus during pregnancy 4 . Despite its public health significance, the specific molecular and cellular basis of HCMV replication in the human placenta and pathogenesis
... associated with poor clinical outcome are unknown. Direct fetal infection is involved in severe cases of neuropathology and infection of the placenta can impair its development and functions resulting in a hypoxic environment 5-8 and stillbirth 6,9,10 . Gestational age at the time of infection is an important determinant of outcome. The rates of virus transmission increase from 30% in first trimester to over 70% in third trimester suggesting different mechanisms for overcoming the placental barrier 2 . Remarkable insights into viral pathogenesis factors that function in the tissue environment have been gained by studying congenitally infected placentas and explants infected by clinical strains ex vivo. Together these studies revealed that direct infection of specialised placental cells and paracrine factors contribute to impaired development and functional defects. Research on congenital HCMV infection has been hindered by the strict species specificity of the human virus. No animal model recapitulates the development and architecture of the human placenta, a hematogenous organ that survives by maternal tolerance of the fetal hemiallograft and performs critical functions throughout pregnancy. Currently, diagnostic indicators for primary and recurrent maternal HCMV infection have not been identified, nor are there any accepted treatments to prevent transmission. Development of a vaccine is in the early stages, long delayed by a poor understanding of the parameters of immune protection and routes of virus spread across the placenta 9,11-13 . As shown in Figure 1, the human placenta is composed of chorionic villi bathed in maternal blood and villi that anchor the placenta in the uterine wall (decidua), attaching the fetus to the mother (panel a1). The individual chorionic villus contains a connective core with blood vessels that carry substances to the fetal circulation (panel a2). Placentation is a stepwise process whereby villus cytotrophoblasts (vCTB) attached to the basement membrane as a polarised epithelium leave the membrane to differentiate along one of two independent pathways depending on their location. In floating villi, they fuse to form a multinucleate synctiotrophoblast (STB) covering attached at one end to the tree-like fetal portion of the placenta. The rest of the villus floats in a stream of maternal blood, which optimises exchange of substances between the maternal and fetal circulation. In the pathway that gives rise to anchoring villi, cytotrophoblasts aggregate into cell columns of non-polarised mononuclear cells that attach to and then invade the uterine wall (iCTBs).