Protection against maternal infection-associated fetal growth restriction: proof-of-concept with a microbial-derived immunomodulator

Infection-associated inflammatory stress during pregnancy is the most common cause of fetal growth restriction. Treatment strategies for protection of at-risk mothers are limited. Employing mouse models, we demonstrate that oral treatment during pregnancy with a microbial-derived immunomodulator (OM85), markedly reduces risk for fetal loss/growth restriction resulting from maternal challenge with bacterial LPS or influenza. Focusing on LPS exposure, we demonstrate that the key molecular indices of maternal inflammatory stress (RANTES, MIP-1a, CCL2, KC, G-CSF) in gestational tissues/serum, are abrogated by OM85 pretreatment. Systems-level analyses of RNASeq data 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 anti-microbial 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. Overall design: Mice were exposed to four treatment conditions (sham control, OM85 pretreatment, LPS challenge, or OM85 pretreatment followed by LPS challenge). Gene expression patterns were profiled in two different tissues (uterus and decidua). There were six animals in each experimental group.

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Scott NM, Lauzon-Joset JF, Jones AC, Mincham KT, Troy NM, Leffler J, Serralha M, Prescott SL, Robertson SA, Pasquali C, Bosco A, Holt PG, Strickland DH