title: 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.
authors.affiliation: Division of Immunobiology.
authors.forename: Monica
authors.initials: M
authors.lastname: Cappelletti
authors.affiliation: Division of Neonatology/Pulmonary Biology, Cincinnati Children's Hospital Research Foundation.
authors.forename: Pietro
authors.initials: P
authors.lastname: Presicce
authors.affiliation: Division of Immunobiology.|Molecular, Cellular and Biochemical Pharmacology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lawson
authors.affiliation: Division of Immunobiology.|Division of Infectious Diseases.
authors.forename: Vandana
authors.initials: V
authors.lastname: Chaturvedi
authors.affiliation: Division of Immunobiology.
authors.forename: Traci E
authors.initials: TE
authors.lastname: Stankiewicz
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Vanoni
authors.affiliation: Division of Immunobiology.
authors.forename: Isaac Tw
authors.initials: IT
authors.lastname: Harley
authors.affiliation: Division of Immunobiology.
authors.forename: Jaclyn W
authors.initials: JW
authors.lastname: McAlees
authors.affiliation: Division of Immunobiology.|Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Giles
authors.affiliation: Division of Immunobiology.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Moreno-Fernandez
authors.affiliation: Division of Immunobiology.
authors.forename: Cesar M
authors.initials: CM
authors.lastname: Rueda
authors.affiliation: Division of Neonatology/Pulmonary Biology, Cincinnati Children's Hospital Research Foundation.
authors.forename: Paranth
authors.initials: P
authors.lastname: Senthamaraikannan
authors.affiliation: Reproductive Sciences.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Karns
authors.affiliation: Division of Immunobiology.
authors.forename: Kasper
authors.initials: K
authors.lastname: Hoebe
authors.affiliation: Division of Immunobiology.
authors.forename: Edith M
authors.initials: EM
authors.lastname: Janssen
authors.affiliation: The Bill & Melinda Gates Foundation, Seattle, Washington, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
authors.affiliation: Division of Immunobiology.
authors.forename: David A
authors.initials: DA
authors.lastname: Hildeman
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
authors.affiliation: Division of Neonatology/Pulmonary Biology, Cincinnati Children's Hospital Research Foundation.
authors.forename: Suhas G
authors.initials: SG
authors.lastname: Kallapur
authors.affiliation: Division of Immunobiology.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
authors.affiliation: Division of Infectious Diseases.
authors.forename: Sing Sing
authors.initials: SS
authors.lastname: Way
authors.affiliation: Division of Immunobiology.
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
mesh_terms: D000818:Animals; D016207:Cytokines / Q000502:physiology; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007249:Inflammation / Q000503:physiopathology*; D007370:Interferon Type I / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D011247:Pregnancy; D047928:Premature Birth; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D007370:Interferon Type I