Type I interferons regulate susceptibility to inflammation-induced preterm birth

Abstract

Preterm birth (PTB) is a leading worldwide cause of morbidity and mortality in infants. Maternal inflammation induced by microbial infection is a critical predisposing factor for PTB. However, biological processes associated with competency of pathogens, including viruses, to induce PTB or sensitize for secondary bacterial infection-driven PTB are unknown. We show that pathogen/pathogen-associated molecular pattern-driven activation of type I IFN/IFN receptor (IFNAR) was sufficient to prime for systemic and uterine proinflammatory chemokine and cytokine production and induction of PTB. Similarly, treatment with recombinant type I IFNs recapitulated such effects by exacerbating proinflammatory cytokine production and reducing the dose of secondary inflammatory challenge required for induction of PTB. Inflammatory challenge-driven induction of PTB was eliminated by defects in type I IFN, TLR, or IL-6 responsiveness, whereas the sequence of type I IFN sensing by IFNAR on hematopoietic cells was essential for regulation of proinflammatory cytokine production. Importantly, we also show that type I IFN priming effects are conserved from mice to nonhuman primates and humans, and expression of both type I IFNs and proinflammatory cytokines is upregulated in human PTB. Thus, activation of the type I IFN/IFNAR axis in pregnancy primes for inflammation-driven PTB and provides an actionable biomarker and therapeutic target for mitigating PTB risk.

Differential outcomes of TLR2 engagement in inflammation-induced preterm birth

“…Gram‐positive bacteria (e.g., Listeria, GBS, and Ureaplasma species) are pathogens commonly associated with PTB . However, competency of certain bacteria to trigger PTB remains unclear.…”

“…Specifically, in such experimental models, the doses of inflammatory ligands employed are high. The intent being to enable 100% parturition incidence in fully backcrossed mice . Notably, that allows investigators to uncover differences between animal genotypes and/or various ligands in comparison to established baseline reads in wild‐type (WT) mice.…”

“…In vivo systemic IL‐6, TNF, and IFN‐γ levels were quantified using in vivo cytokine capture assay . Briefly, biotinylated capture antibodies (eBioscience) were injected i.p.…”

“…Infections by Gram‐positive bacteria have the most deleterious outcomes during pregnancy . Listeria monocytogenes , a Gram‐positive bacteria and common contaminant of a variety of raw foods, has tropism for the placenta and is known to cause PTB in humans and mice . Moreover, Group B streptococci (GBS), the β‐hemolytic, Gram‐positive constituent of the normal vaginal microflora, is frequently associated with PTB .…”

Magnesium sulfate differentially modulates fetal membrane inflammation in a time‐dependent manner

“…More recently, a role for viral infection in the predisposition of bacterial-induced preterm birth has been examined using experimental models 8–10 . Infection and/or inflammation of the fetal membranes (chorioamnionitis) is an important risk factor 11 , complicating 40-70% of spontaneous premature births 12 .…”