SHORT COMMUNICATION

Placental Viral Infection Sensitizes to Endotoxin-Induced Pre-Term Labor: A Double Hit Hypothesis

  1. Ingrid Cardenas1,
  2. Gil Mor1,
  3. Paulomi Aldo1,
  4. Sabine M. Lang2,
  5. Paul Stabach2,
  6. Andrew Sharp1,
  7. Roberto Romero3,
  8. Shali Mazaki-Tovi3,
  9. MariaTeresa Gervasi4,
  10. Robert E. Means2

Article first published online: 13 AUG 2010

DOI: 10.1111/j.1600-0897.2010.00908.x

Issue

American Journal of Reproductive Immunology

American Journal of Reproductive Immunology

Volume 65, Issue 2, pages 110–117, February 2011

Additional Information

How to Cite

Cardenas, I., Mor, G., Aldo, P., Lang, S. M., Stabach, P., Sharp, A., Romero, R., Mazaki-Tovi, S., Gervasi, M. and Means, R. E. (2011), Placental Viral Infection Sensitizes to Endotoxin-Induced Pre-Term Labor: A Double Hit Hypothesis. American Journal of Reproductive Immunology, 65: 110–117. doi: 10.1111/j.1600-0897.2010.00908.x

Author Information

  1. 1

    Department of Obstetrics Gynecology and Reproductive Sciences, Reproductive Immunology Unit, School of Medicine, Yale University, USA

  2. 2

    Department of Pathology; School of Medicine, Yale University, USA

  3. 3

    Wayne State University, Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Detroit

  4. 4

    Department of Obstetrics and Gynecology, Azienda Ospedaliera of Padova, Padova, Italy

*Gil Mor, Department of Obstetrics, Gynecology & Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, 333 Cedar St., LSOG 305A, New Haven, CT 06520, USA. E-mail: gil.mor@yale.edu

Publication History

  1. Issue published online: 6 JAN 2011
  2. Article first published online: 13 AUG 2010
  3. Submitted June 28, 2010; accepted July 2, 2010.

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Keywords:

  • Double hit hypothesis;
  • lipopolysaccharide;
  • placenta;
  • toll-like receptors;
  • trophoblast;
  • viral infection

Citation Cardenas I, Mor G, Aldo P, Lang SM, Stabach P, Sharp A, Romero R, Mazaki-Tovi S, Gervasi MTeresa, Means RE. Placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis. Am J Reprod Immunol 2011; 65: 110–117

Problem  Among pregnant women, acquired viral infections with a concurrent bacterial infection is a detrimental factor associated to poor prognosis. We evaluate the effect of a viral infection that does not lead to pre-term labor on the response to low doses of lipopolysaccharide (LPS). Our objectives were (i) to characterize the effect of a viral infection concurrent with exposure to microbial products on pregnancy outcome and (ii) to characterize the placental and fetal immune responses to the viral sensitization to LPS.

Method  C57B/6 wild-type mice were injected with murine gammaherpesvirus 68 (MHV68) at E8.5. Either PBS or LPS was injected i.p. at E15.5. Pregnancy outcome and cytokine/chemokine profile from implantation sites were analyzed by multiplex.

Results  LPS treatment of MHV-68-infected animals induced pre-term delivery and fetal death in 100% of the mice. Pre-term labor was characterized by a upregulation of pro-inflammatory cytokines and chemokines in both placenta and decidua. Similar profiles were observed from MHV-68-infected human primary trophoblast and trophoblast cell lines in response to LPS.

Conclusion  We describe for the first time that a sub-clinical viral infection in pregnant mice might sensitize to a bacterial infection leading to pre-term delivery. We propose the ‘Double Hit Hypothesis’ where the presence of a viral infection enhances the effect of bacterial products during pregnancy leading not only to pre-term labor but likely larger adverse outcomes.

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