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.

Transplacental innate immune training via maternal microbial exposure: the XBP1-ERN1 axis in programming dendritic cell precursors

“…In summary, the data presented here builds on forerunner human (4,24) and experimental animal (8,34,35) studies providing evidence that non-pathogenic maternal microbial-associated exposures during pregnancy can be transcribed transplacentally into beneficial immune training signals for the developing fetus. We provide direct evidence that maternal OM-85 treatment during pregnancy transplacentally accelerates functional immunocompetence of fetal bone marrow cDCs and for the first time identify the transcription factor XBP1 as a putative driver of this immune training mechanism.…”

Transplacental protection against asthma by maternal treatment with a bacterial-derived immunomodulatory agent

“…We posited that treatment of pregnant mice with the microbial-derived immunomodulatory agent OM85 would enhance the resistance of their offspring to development of experimental atopic asthma during the early post-weaning period. To test this hypothesis, we utilised an OM85 treatment protocol we have recently demonstrated to protect pregnant mice and their fetuses against the toxic effects of bacterial and viral infections 13 , comprising oral administration of OM85 from gestation day 9.5-17.5, followed by natural delivery of offspring 2-3 days later. Age-matched offspring from OM85 treated and untreated control mothers were sensitized at weaning (21 days of age) and aerosol challenged as per Fig.…”

“…Previous studies from our lab and others have identified mucosal homing Tregs as a potential target for OM85-mediated treatment effects in adult non-pregnant 44,45 and pregnant 13 animals, prompting an initial focus on this population. We accordingly phenotyped the T-cell response within the airways compartment using multi-colour flow cytometry.…”

“…Moreover, susceptibility to respiratory infections exemplified by influenza virus and its associated symptom severity is likewise increased during pregnancy 53,54 , and the latter (along with bacterial infections) is a risk factor for fetal growth restriction 55 which in turn is associated with increased risk for postnatal development of a range of non-communicable diseases including asthma 56,57 . In this regard, our forerunner studies on OM85 use in pregnant mice have demonstrated strong protection against the effects of pathogen-associated challenge during pregnancy employing high dose LPS or live influenza, both with respect to preservation of pregnancy per se, and maintenance of normal maternal weight gain and associated fetal growth trajectories 13 . In this system the principal treatment effect of OM85 involved selective attenuation within gestational tissues of the intensity of the pro-inflammatory (particularly TNFα/IL-1/IL-6)…”

“…In preliminary investigations to establish the safety of OM85 use during pregnancy we demonstrated that maternal treatment with this agent enhanced homeostatic control of innate immune and inflammatory functions in gestational tissues at baseline and in the face of challenge with microbial pathogens including live influenza infection and the bacterial mimic LPS. Specifically, OM85 treatment attenuated inflammatory symptoms (which are typically exaggerated during pregnancy) and protected against fetal growth restriction and/or pregnancy termination which can follow maternal infection 13 . In the study presented here we focus on the effects of maternal OM85 treatment during healthy pregnancy on the immunocompetence of offspring during the postnatal weanling period when immune functions are typically developmentally compromised.…”