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

Abstract

Non-pathogenic environmental microbial exposures during pregnancy can be transplacentally transcribed into beneficial immune training signals for the developing fetus.These signals equip offspring for more rapid adaptation to the microbe-rich postnatal environment by optimising immunoregulatory innate cell function. We have previously identified that maternal treatment with a microbial-derived therapeutic (OM-85) can protect offspring against allergic airways inflammation. Here, we show that oral treatment of pregnant mice with OM-85 induces transplacental signals that manifest in fetal bone marrow as an enriched population of conventional dendric cells (cDC) displaying enhanced functional maturation. Moreover, the myeloid progenitor populations directly upstream of this cDC pool were significantly boosted in response to maternal treatment. Transcriptomic analysis of fetal bone marrow identified maternal OM-85-induced activation of X-box binding protein 1 (XBP1), with upregulation of active XBP1 restricted to cDC precursors. These data provide direct evidence that transplacental immune training with a microbial-derived therapeutic can accelerate functional immune competence of the fetal bone marrow myeloid compartment. KTM, PGH and DHS designed the study. KTM, MB , NMS and JFLJ performed the experiments. KTM, ACJ, MB and DHS analysed the data. PAS and AB contributed to the project design and discussions on data interpretation. KTM, PAS, PGH and DHS wrote the manuscript. All authors reviewed the final version of the manuscript.

Transplacental Innate Immune Training via Maternal Microbial Exposure: Role of XBP1-ERN1 Axis in Dendritic Cell Precursor Programming

“…The authors wish to acknowledge the animal technicians at the Telethon Kids Institute Bioresources Centre. This manuscript has been released as a pre-print at bioRxiv (76).…”

Protection against neonatal respiratory viral infection via maternal treatment during pregnancy with the benign immune training agent OM‐85

“…Given our previous findings of enhanced myelopoiesis in foetal bone marrow following OM-85 treatment of pregnant mice, 30 we first sought to determine the influence of maternal OM-85 treatment on baseline postnatal development of immune cell populations in the lungs of their offspring. Time-mated pregnant mice were orally treated with OM-85 from gestation day (GD) 0.5-17.5, followed by natural term delivery of offspring 2-3 days later (%GD20.5).…”

“…This was accompanied by enhanced capacity of regulatory T cells (Treg) to regulate the intensity/duration of allergic airway inflammatory responses. 30,31 Given that similar DC/Tregassociated mechanisms are central to protection against infection-induced inflammatory tissue damage in the lower respiratory tract, we posited that maternal OM-85 treatment could also enhance resistance to a lethal viral LRI in the offspring during the highly vulnerable neonatal period, and testing this hypothesis was the focus of the experiments reported below. Neonatal offspring from mothers treated with oral OM-85 during pregnancy were infected with a mouseadapted rhinovirus (vMC 0 ) at 2 days of age, and the clinical, cellular and targeted gene expression response within the neonatal lungs was evaluated during the acute, peak and resolution phases of infection.…”

Vertical Stratification in Urban Green Space Aerobiomes

“…The presence of vertical stratification of bacterial diversity in the aerobiome could have important implications for human health. Indeed, exposure to environmental microbes is thought to prime and "educate" the immune system (Belkaid and Hand 2014;Hanski 2014;Mincham et al 2020) particularly in early life, and a recent mouse study suggests that exposure to environmental microbes such as the butyrate-producer Kineothrix alysoides could also have anxiolytic (anxiety-reducing) effects (Liddicoat et al 2019). The vertical stratification concept could also be important for exposome researchers, who investigate the types and methods of exposures to both endogenous and exogenous chemical composites (including microbes and their biological compounds across the life course) (Escher et al 2017;Daiber et al 2019;McCall et al 2019).…”