Cytomegalovirus Infection in the Human Placenta: Maternal Immunity and Developmentally Regulated Receptors on Trophoblasts Converge

  • L. Pereira
  • E. Maidji
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 325)

During human pregnancy, CMV infects the uterine-placental interface with varied outcomes from fetal intrauterine growth restriction to permanent birth defects, depending on the level of maternal immunity and gestational age. Virus spreads from infected uterine blood vessels, amplifies by replicating in decidual cells, and disseminates to the placenta in immune complexes. Cytotrophoblasts – epithelial cells of the placenta – differentiate along two distinct pathways. In the first, cells fuse into syncytiotrophoblasts covering the surface of chorionic villi that transport substances from the maternal to fetal bloodstream. In the second, cells invade the uterine interstitium and blood vessels, remodel the vasculature and form anchoring villi. CMV initiates replication in cytotrophoblast progenitor cells of floating villi, whereas syncytiotrophoblasts are spared. This extraordinary pattern of focal infection in underlying cells hinges on virion receptors being upregulated as villous cytotrophoblasts begin to differentiate. Expression of developmentally regulated receptors could explain viral replication in spatially distinct maternal and fetal compartments. Reduced invasiveness of infected cells could impair remodeling of the uterine vasculature, restrict maternal blood flow and access of the fetus to nutrients causing intrauterine growth restriction.


Human Placenta Cytomegalovirus Infection Decidual Cell Maternal Immunity Villous Cytotrophoblasts 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barker DJ (1999) Fetal origins of cardiovascular disease. Ann Med 31 Suppl 1:3–6PubMedGoogle Scholar
  2. Benirschke K, Kaufmann P (2000) Pathology of the human placenta. Springer, Berlin, New York, HeidelbergGoogle Scholar
  3. Berinstein A, Roivainen M, Hovi T, Mason PW, Baxt B (1995) Antibodies to the vitronectin receptor (integrin alpha V beta 3) inhibit binding and infection of foot-and-mouth disease virus to cultured cells. J Virol 69:2664–2666PubMedGoogle Scholar
  4. Britt WJ (1999) Congenital cytomegalovirus infection. In: Hitchcock PJ, MacKay HT, Wasserheit JN (eds) Sexually transmitted diseases and adverse outcomes of pregnancy. ASM Press, Washington, DC, pp 269–281Google Scholar
  5. Cetin I, Foidart JM, Miozzo M, Raun T, Jansson T, Tsatsaris V, Reik W, Cross J, Hauguel-De-Mouzon S, Illsley N, Kingdom J, Huppertz B (2004) Fetal growth restriction: a workshop report. Placenta 25:753–757PubMedCrossRefGoogle Scholar
  6. Chang WL, Baumgarth N, Yu D, Barry PA (2004) Human cytomegalovirus-encoded interleukin-10 homolog inhibits maturation of dendritic cells and alters their functionality. J Virol 78:8720–8731PubMedCrossRefGoogle Scholar
  7. Cross JC, Werb Z, Fisher SJ (1994) Implantation and the placenta: key pieces of the development puzzle. Science 266:1508–1518PubMedCrossRefGoogle Scholar
  8. Damsky CH, Fisher SJ (1998) Trophoblast pseudo-vasculogenesis: faking it with endothelial adhesion receptors. Curr Opin Cell Biol 10:660–666PubMedCrossRefGoogle Scholar
  9. Damsky CH, Fitzgerald ML, Fisher SJ (1992) Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo. J Clin Invest 89:210–222PubMedCrossRefGoogle Scholar
  10. Damsky CH, Librach C, Lim KH, Fitzgerald ML, McMaster MT, Janatpour M, Zhou Y, Logan SK, Fisher SJ (1994) Integrin switching regulates normal trophoblast invasion. Development 120:3657–3666PubMedGoogle Scholar
  11. Feire AL, Koss H, Compton T (2004) Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain. Proc Natl Acad Sci U S A 101:15470–15475PubMedCrossRefGoogle Scholar
  12. Fisher S, Genbacev O, Maidji E, Pereira L (2000) Human cytomegalovirus infection of placental cytotrophoblasts in vitro and in utero: implications for transmission and pathogenesis. J Virol 74:6808–6820PubMedCrossRefGoogle Scholar
  13. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA (1992) The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med 326:663–667PubMedGoogle Scholar
  14. Fowler KB, Stagno S, Pass RF (2003) Maternal immunity and prevention of congenital cytomegalovirus infection. JAMA 289:1008–1011PubMedCrossRefGoogle Scholar
  15. Garcia AG, Fonseca EF, Marques RL, Lobato YY (1989) Placental morphology in cytomegalovirus infection. Placenta 10:1–18PubMedCrossRefGoogle Scholar
  16. Genbacev O, Krtolica A, Kaelin W, Fisher SJ (2001) Human cytotrophoblast expression of the von Hippel-Lindau protein is downregulated during uterine invasion in situ and upregulated by hypoxia in vitro. Dev Biol 233:526–536PubMedCrossRefGoogle Scholar
  17. Halwachs-Baumann G, Wilders-Truschnig M, Desoye G, Hahn T, Kiesel L, Klingel K, Rieger P, Jahn G, Sinzger C (1998) Human trophoblast cells are permissive to the complete replicative cycle of human cytomegalovirus. J Virol 72:7598–7602PubMedGoogle Scholar
  18. Hemmings DG, Kilani R, Nykiforuk C, Preiksaitis J, Guilbert LJ (1998) Permissive cytomegalovirus infection of primary villous term and first trimester trophoblasts. J Virol 72:4970–4979PubMedGoogle Scholar
  19. Jackson T, Sheppard D, Denyer M, Blakemore W, King AM (2000) The epithelial integrin alphavbeta6 is a receptor for foot-and-mouth disease virus. J Virol 74:4949–4956PubMedCrossRefGoogle Scholar
  20. Janatpour MJ, McMaster MT, Genbacev O, Zhou Y, Dong J, Cross JC, Israel MA, Fisher SJ (2000) Id-2 regulates critical aspects of human cytotrophoblast differentiation, invasion and migration. Development 127:549–558PubMedGoogle Scholar
  21. Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S (2000) Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci USA 97:1695–1700PubMedCrossRefGoogle Scholar
  22. Kumazaki K, Ozono K, Yahara T, Wada Y, Suehara N, Takeuchi M, Nakayama M (2002) Detection of cytomegalovirus DNA in human placenta. J Med Virol 68:363–369PubMedCrossRefGoogle Scholar
  23. Lau C, Rogers JM (2004) Embryonic and fetal programming of physiological disorders in adulthood. Birth Defects Res C Embryo Today 72:300–312PubMedCrossRefGoogle Scholar
  24. Librach CL, Werb Z, Fitzgerald ML, Chiu K, Corwin NM, Esteves RA, Grobelny D, Galardy R, Damsky CH, Fisher SJ (1991) 92-kD type IV collagenase mediates invasion of human cytotrophoblasts. J Cell Biol 113:437–449PubMedCrossRefGoogle Scholar
  25. Maidji E, McDonagh S, Genbacev O, Tabata T, Pereira L (2006) Maternal antibodies enhance or prevent cytomegalovirus infection in the placenta by neonatal fc receptor-mediated transcytosis. Am J Pathol 168:1210–1226PubMedCrossRefGoogle Scholar
  26. Maidji E, Genbacev O, Chang HT, Pereira L (2007) Developmental regulation of human cytomegalovirus receptors in cytotrophoblasts correlates with distinct replication sites in the placenta. J Virol 81:4701–4712PubMedCrossRefGoogle Scholar
  27. McDonagh S, Maidji E, Ma W, Chang HT, Fisher S, Pereira L (2004) Viral and bacterial pathogens at the maternal-fetal interface. J Infect Dis 190:826–834PubMedCrossRefGoogle Scholar
  28. McDonagh S, Maidji E, Chang H-T, Pereira L (2006) Patterns of human cytomegalovirus infection in term placentas: a preliminary analysis. J Clin Virol 35:210–215PubMedCrossRefGoogle Scholar
  29. Muhlemann K, Miller RK, Metlay L, Menegus MA (1992) Cytomegalovirus infection of the human placenta: an immunocytochemical study. Human Pathol 23:1234–1237CrossRefGoogle Scholar
  30. Nigro G, La Torre R, Anceschi MM, Mazzocco M, Cosmi EV (1999) Hyperimmunoglobulin therapy for a twin fetus with cytomegalovirus infection and growth restriction. Am J Obstet Gynecol 180:1222–1226PubMedCrossRefGoogle Scholar
  31. Nigro G, Adler SP, La Torre R, Best AM (2005) Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 353:1350–1362PubMedCrossRefGoogle Scholar
  32. Norwitz ER, Schust DJ, Fisher SJ (2001) Implantation and the survival of early pregnancy. N Engl J Med 345:1400–1408PubMedCrossRefGoogle Scholar
  33. Pereira L, Maidji E, McDonagh S, Genbacev O, Fisher S (2003) Human cytomegalovirus transmission from the uterus to the placenta correlates with the presence of pathogenic bacteria and maternal immunity. J Virol 77:13301–13314PubMedCrossRefGoogle Scholar
  34. Pereira L, Maidji E, McDonagh S, Tabata T (2005) Insights into viral transmission at the uterine-placental interface. Trends Microbiol 13:164–174PubMedCrossRefGoogle Scholar
  35. Reyes L, Manalich R (2005) Long-term consequences of low birth weight. Kidney Int Suppl: S107–S111Google Scholar
  36. Roth I, Fisher SJ (1999) IL-10 is an autocrine inhibitor of human placental cytotrophoblast MMP-9 production and invasion. Dev Biol 205:194–204PubMedCrossRefGoogle Scholar
  37. Roth I, Corry DB, Locksley RM, Abrams JS, Litton MJ, Fisher SJ (1996) Human placental cytotrophoblasts produce the immunosuppressive cytokine interleukin 10. J Exp Med 184:539–548PubMedCrossRefGoogle Scholar
  38. Simister NE, Story CM, Chen HL, Hunt JS (1996) An IgG-transporting Fc receptor expressed in the syncytiotrophoblast of human placenta. Eur J Immunol 26:1527–1531PubMedCrossRefGoogle Scholar
  39. Sinzger C, Müntefering H, Löning T, Stöss H, Plachter B, Jahn G (1993) Cell types infected in human cytomegalovirus placentitis identified by immunohistochemical double staining. Virchows Archiv A Pathol Anat Histopathol 423:249–256CrossRefGoogle Scholar
  40. Spencer JV, Lockridge KM, Barry PA, Lin G, Tsang M, Penfold ME, Schall TJ (2002) Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. J Virol 76:1285–1292PubMedGoogle Scholar
  41. Stagno S, Pass RF, Cloud G, Britt WJ, Henderson RE, Walton PD, Veren DA, Page F, Alford CA (1986) Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome. JAMA 256:1904–1908PubMedCrossRefGoogle Scholar
  42. Story CM, Mikulska JE, Simister NE (1994) A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus. J Exp Med 180:2377–2381PubMedCrossRefGoogle Scholar
  43. Tabata T, McDonagh S, Kawakatsu H, Pereira L (2007) Cytotrophoblasts infected with a pathogenic human cytomegalovirus strain dysregulate cell-matrix and cell-cell adhesion molecules: a quantitative analysis. Placenta 28:527–537PubMedCrossRefGoogle Scholar
  44. Trincado DE, Munro SC, Camaris C, Rawlinson WD (2005) Highly sensitive detection and localization of maternally acquired human cytomegalovirus in placental tissue by in situ polymerase chain reaction. J Infect Dis 192:650–657PubMedCrossRefGoogle Scholar
  45. Wang X, Huong SM, Chiu ML, Raab-Traub N, Huang ES (2003) Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 424:456–461PubMedCrossRefGoogle Scholar
  46. Wang X, Huang DY, Huong SM, Huang ES (2005) Integrin alphavbeta3 is a coreceptor for human cytomegalovirus. Nat Med 11:515–521PubMedCrossRefGoogle Scholar
  47. Winn VD, Haimov-Kochman R, Paquet AC, Yang YJ, Madhusudhan MS, Gormley M, Feng KT, Bernlohr DA, McDonagh S, Pereira L, Sali A, Fisher SJ (2007) Gene expression profiling of the human maternal–fetal interface reveals dramatic changes between midgestation and term. Endocrinology 148:1059–1079PubMedCrossRefGoogle Scholar
  48. Yamamoto-Tabata T, McDonagh S, Chang H-T, Fisher S, Pereira L (2004) Human cytomegalovirus interleukin-10 downregulates matrix metalloproteinase activity and impairs endothelial cell migration and placental cytotrophoblast invasiveness in vitro. J Virol 78:2831–2840PubMedCrossRefGoogle Scholar
  49. Zhou Y, Fisher SJ, Janatpour M, Genbacev O, Dejana E, Wheelock M, Damsky CH (1997) Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J Clin Invest 99:2139–2151PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • L. Pereira
    • 1
  • E. Maidji
    • 1
  1. 1.Department of Cell and Tissue BiologyUniversity of California San FranciscoSan FranciscoUSA

Personalised recommendations