ProblemPreterm birth (PTB) affects approximately 12% of pregnancies and at least 50% of cases have no known risk factors. We hypothesize that subclinical viral infections of the placenta are a factor sensitizing women to intrauterine bacterial infection. Specifically, we propose that viral-induced placental IFN- inhibition results in a robust inflammatory response to low concentrations of bacteria.MethodsHuman trophoblast SW.71, C57BL/6, and interferon (IFN) receptor knockout animals were used to determine IFN function. Illumina and Bio-Rad microarrays identified pathways.ResultsInhibiting the IFN- pathway resulted in a significant increase in inflammatory cytokines such as IL-1B in response to LPS. Twist was positively correlated with IFN- expression and STAT3 phosphorylation and overexpressing Twist reduced IL-1B. Treating IFNAR-/- mice with low-dose LPS at E15.5 caused preterm birth.ConclusionIFN- was identified as a key modulator of placental inflammation and, importantly, is commonly affected by viruses. We propose dysregulation of IFN- is a major determinant for preterm birth associated with polymicrobial infection.