Villous Cytotrophoblasts Express EGFR and Upregulate Integrin aV

In naturally infected placentas, CMV replicates in underlying cytotrophoblast progenitors but not in syncytiotrophoblasts covering the villus surface (Fisher et al. 2000; Pereira et al. 2003; Maidji et al. 2007). CMV gB was repeatedly detected in a punctate staining pattern in syncytiotrophoblasts of immune donors, but viral replication proteins were absent. Notably, syncytiotrophoblasts expressed EGFR in apical microvilli, but neither integrin aipi nor aV was detected. Occasionally, gB appeared in a punctate pattern in cytotrophoblast progenitors reactive with antibodies to EGFR and integrin aV, but aipi was not detected. Frequently, virion capsids were found clustered near the microvillous surface of syncytiotrophoblasts, and CMV DNA was detected by in situ hybridization. These findings indicated that viral capsids, DNA and gB were present without replication in placentas that contained high-titer neutralizing antibodies, sometimes in the presence of other pathogens (McDonagh et al. 2004).

Examination of CMV receptors expressed in cytotrophoblasts of villus explants infected with a recombinant Toledor ec virus encoding green fluorescent protein in the villus explant model (Fig. 2a) confirmed that the receptors were expressed in infected cells. Virions attached in a punctate (green) pattern to apical microvilli of syncytiotrophoblasts, and some internalized but did not replicate (Fig. 2b). Although syncytiotrophoblasts express EGFR, functional coreceptors are missing. Even so, virion-containing immune complexes internalize and colo-calize with caveolin-i-containing vesicular compartments that were not detected


Fig. 2 CMV replicates in cytotrophoblasts expressing EGFR and aV integrin in villous explants infected in vitro. a Diagram shows focal infection in a floating villus. The blue field represents the localization of CMV structural and replication proteins in panels b and c. Explants were fixed at 24 h postinfection. b Toledorec virions bound to apical microvilli of syncytiotrophoblasts (ST). Selected cytotrophoblasts (CTB), but not syncytiotrophoblasts, reacted with antibody to aV integrin (red). c Underlying cytotrophoblasts stained intensely with EGFR-specific antibody (red); replicating Toledorec broadly expressed green fluorescent protein in nuclei of infected cells. Nuclei were counterstained with TO-PRO-3 iodide (blue). d Villous cytotrophoblasts infected with Toledor ec simultaneously expressed aV integrin (red) and EGFR (blue)

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