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Researchers investigated how viral infections trigger inflammation in fetal membranes that can lead to preterm birth. They found that when fetal membranes are exposed to a viral mimic, they package specific microRNAs (particularly miR-146a-3p) into small extracellular vesicles, which then activate immune receptors TLR7 and TLR8 to propagate inflammatory responses. This mechanism differs from bacterial infection pathways but results in similar pro-inflammatory outcomes including elevated IL-6, IL-8, and IL-1β secretion.
Why it matters
Understanding how viral infections contribute to preterm birth through this extracellular vesicle-mediated pathway could lead to new therapeutic targets for preventing virus-associated preterm labor and reducing neonatal morbidity. This research fills an important knowledge gap since viral infection mechanisms in pregnancy complications have been less studied than bacterial ones.
Understand the Science
by Hanah M. Georges, Abigail C. Fischer, Paloma Casanova, Vikki M. Abrahams
Maternal infection and chorioamnionitis are one of the leading causes of preterm birth and neonatal morbidity. The relationship and mechanisms linking bacterial infections and preterm labor are well researched, however, less is known about the mechanisms involved in how viral infections contribute to preterm labor. Previous work from our group demonstrated that following bacterial triggers, fetal membranes (FMs) express elevated miR-146a-3p which in turn acts as an intermediate danger signal by activating TLR8 to induce a robust inflammatory response. Using an established FM explant model system, the role of this and other TLR7/8-activating miRs in the propagation of viral-induced inflammation was investigated. Following exposure to the viral dsRNA mimic and TLR3 agonist, Poly(I:C), expression of FM tissue TLR7/8-activating miRs (miR-146a-3p, miR-21a, miR-29a, and Let7b) were not elevated. Despite this, in response to Poly(I:C), elevated FM secretion of pro-inflammatory IL-6 and IL-8, and IL-1β was TLR7- and TLR8-dependent. To investigate alternative methods of miR delivery, small extracellular vesicles (sEVs) from FM supernatants were isolated and found to contain elevated levels of miR-146a-3p and miR-21a under Poly(I:C) conditions. Furthermore, Poly(I:C)-induced IL-6 and IL-8 responses were reduced in the presence of an inhibitor of sEV biogenesis/release, and IL-6 and IL-1β production was reduced in the presence of a miR-146a-3p inhibitor. Together, these data suggests that sEVs produced from virally-stimulated human FMs contain and deliver elevated miR-146a-3p which acts as a danger signal to drive perpetuate inflammation via TLR7 and TLR8 activation. This work demonstrates a novel and important role for sEV packaged TLR7/8 activating-miR-146a-3p in FM inflammatory responses to viral infections.