Karen Racicot1,2, Ja Young Kwon1,3, Paulomi Aldo1, Vikki Abrahams1, Ayman El-Guindy4, Roberto Romero5, Gil Mor1. 1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA. 2. Department of OB/GYN, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA. 3. Department of OB/GYN, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea. 4. Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA. 5. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Detroit, MI, USA.
Abstract
PROBLEM: Preterm 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-β inhibition results in a robust inflammatory response to low concentrations of bacteria. METHODS: Human trophoblast SW.71, C57BL/6, and interferon (IFN) receptor knockout animals were used to determine IFN function. Illumina and Bio-Rad microarrays identified pathways. RESULTS: Inhibiting the IFN-β pathway resulted in a significant increase in inflammatory cytokines such as IL-1B in response to LPS. Twist was positively correlated with IFN-β expression and STAT3 phosphorylation and overexpressing Twist reduced IL-1B. Treating IFNAR-/- mice with low-dose LPS at E15.5 caused preterm birth. CONCLUSION: IFN-β was identified as a key modulator of placental inflammation and, importantly, is commonly affected by viruses. We propose dysregulation of IFN-β is a major determinant for preterm birth associated with polymicrobial infection.
PROBLEM: Preterm 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-β inhibition results in a robust inflammatory response to low concentrations of bacteria. METHODS:Human trophoblast SW.71, C57BL/6, and interferon (IFN) receptor knockout animals were used to determine IFN function. Illumina and Bio-Rad microarrays identified pathways. RESULTS: Inhibiting the IFN-β pathway resulted in a significant increase in inflammatory cytokines such as IL-1B in response to LPS. Twist was positively correlated with IFN-β expression and STAT3 phosphorylation and overexpressing Twist reduced IL-1B. Treating IFNAR-/-mice with low-dose LPS at E15.5 caused preterm birth. CONCLUSION: IFN-β was identified as a key modulator of placental inflammation and, importantly, is commonly affected by viruses. We propose dysregulation of IFN-β is a major determinant for preterm birth associated with polymicrobial infection.
Authors: Julie A Potter; Mancy Tong; Paulomi Aldo; Ja Young Kwon; Mary Pitruzzello; Gil Mor; Vikki M Abrahams Journal: J Reprod Immunol Date: 2020-04-08 Impact factor: 4.054
Authors: Ângela C Crespo; Anita van der Zwan; João Ramalho-Santos; Jack L Strominger; Tamara Tilburgs Journal: J Reprod Immunol Date: 2016-08-02 Impact factor: 4.054