title: Protection against maternal infection-associated fetal growth restriction: proof-of-concept with a microbial-derived immunomodulator.
abstract: Infection-associated inflammatory stress during pregnancy is the most common cause of fetal growth restriction and/or miscarriage. Treatment strategies for protection of at-risk mothers are limited to a narrow range of vaccines, which do not cover the bulk of the common pathogens most frequently encountered. Using mouse models, we demonstrate that oral treatment during pregnancy with a microbial-derived immunomodulator (OM85), currently used clinically for attenuation of infection-associated airway inflammatory symptoms in infants-adults, markedly reduces risk for fetal loss/growth restriction resulting from maternal challenge with bacterial lipopolysaccharide or influenza. Focusing on LPS exposure, we demonstrate that the key molecular indices of maternal inflammatory stress, notably high levels of RANTES, MIP-1α, CCL2, KC, and G-CSF (granulocyte colony-stimulating factor) in gestational tissues/serum, are abrogated by OM85 pretreatment. Systems-level analyses conducted in parallel using RNASeq revealed that OM85 pretreatment selectively tunes LPS-induced activation in maternal gestational tissues for attenuated expression of TNF, IL1, and IFNG-driven proinflammatory networks, without constraining Type1-IFN-associated networks central to first-line antimicrobial defense. This study suggests that broad-spectrum protection-of-pregnancy against infection-associated inflammatory stress, without compromising capacity for efficient pathogen eradication, represents an achievable therapeutic goal.
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: N M
authors.initials: NM
authors.lastname: Scott
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: J F
authors.initials: JF
authors.lastname: Lauzon-Joset
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: Jones
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: K T
authors.initials: KT
authors.lastname: Mincham
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: N M
authors.initials: NM
authors.lastname: Troy
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Leffler
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Serralha
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.|School of Paediatrics and Child Health, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: Prescott
authors.affiliation: Robinson Research Institute and School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: Robertson
authors.affiliation: OM Pharma, SA Geneva, Geneva, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Pasquali
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Bosco
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: P G
authors.initials: PG
authors.lastname: Holt
authors.affiliation: Telethon Kids Institute, The University of Western Australia, West Perth, Western Australia, Australia.
authors.forename: D H
authors.initials: DH
authors.lastname: Strickland
mesh_terms: D000022:Abortion, Spontaneous / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001424:Bacterial Infections / Q000150:complications / Q000276:immunology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D047109:Fetal Development; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D009980:Influenza A virus / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000276:immunology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology* / Q000517:prevention & control; D000075082:Proof of Concept Study
chemical_list: D000942:Antigens, Bacterial; D007155:Immunologic Factors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides