Placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Cardenas
Ingrid
I
Department of Obstetrics Gynecology and Reproductive Sciences, Reproductive Immunology Unit, School of Medicine, Yale University, New Haven, CT 06520, USA.
Mor
Gil
G
Aldo
Paulomi
P
Lang
Sabine M
SM
Stabach
Paul
P
Sharp
Andrew
A
Romero
Roberto
R
Mazaki-Tovi
Shali
S
Gervasi
MariaTeresa
M
Means
Robert E
RE
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology / Q000382:microbiology; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D005313:Fetal Death; D006566:Herpesviridae Infections / Q000821:virology; D006801:Humans; D007751:Labor, Induced; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D007752:Obstetric Labor, Premature / Q000209:etiology*; D010920:Placenta / Q000187:drug effects / Q000821:virology; D010922:Placenta Diseases / Q000276:immunology / Q000382:microbiology / Q000821:virology*; D011247:Pregnancy; D018144:Rhadinovirus / Q000472:pathogenicity*; D014412:Tumor Virus Infections / Q000821:virology
D004731:Endotoxins; D008070:Lipopolysaccharides