Viral infection sensitizes human fetal membranes to bacterial lipopolysaccharide by MERTK inhibition and inflammasome activation

Sarah N. Cross, Julie A. Potter, Paulomi Aldo, Ja Young Kwon, Mary Pitruzzello, Mancy Tong, Seth Guller, Carla V. Rothlin, Gil Mor, Vikki M. Abrahams

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Chorioamnionitis, premature rupture of fetal membranes (FMs), and subsequent preterm birth are associated with local infection and inflammation, particularly IL-1β production. Although bacterial infections are commonly identified, other microorganisms may play a role in the pathogenesis. Because viral pandemics, such as influenza, Ebola, and Zika, are becoming more common, and pregnant women are at increased risk for associated complications, this study evaluated the impact that viral infection had on human FM innate immune responses. This study shows that a herpes viral infection of FMs sensitizes the tissue to low levels of bacterial LPS, giving rise to an exaggerated IL-1β response. Using an ex vivo human FM explant system and an in vivo mouse model of pregnancy, we report that the mechanism by which this aggravated inflammation arises is through the inhibition of the TAM receptor, MERTK, and activation of the inflammasome. The TAM receptor ligand, growth arrest specific 6, re-establishes the normal FM response to LPS by restoring and augmenting TAM receptor and ligand expression, as well as by preventing the exacerbated IL-1β processing and secretion. These findings indicate a novel mechanism by which viruses alter normal FM immune responses to bacteria, potentially giving rise to adverse pregnancy outcomes.

Original languageEnglish (US)
Pages (from-to)2885-2895
Number of pages11
JournalJournal of Immunology
Volume199
Issue number8
DOIs
StatePublished - Oct 15 2017

Bibliographical note

Funding Information:
This work was supported in part by Grants R01AI121183 (to V.M.A.) and R56AI124356 (to G.M.) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health and by the McKern Scholar Award for Perinatal Research (to V.M.A.).

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