No 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.

Appropriate innate immune function is essential to limit pathogenesis and severity of severe lower respiratory infections (sLRI) during infancy, a leading cause of hospitalization and risk factor for subsequent asthma in this age group. Employing a systems biology approach to analysis of multi-omic profiles generated from a high-risk cohort (n=50), we found that the intensity of activation of an LPS-induced interferon gene network at birth was predictive of sLRI risk in infancy (AUC=0.724). Connectivity patterns within this network were stronger among susceptible individuals, and a systems biology approach identified IRF1 as a putative master regulator of this response. These findings were specific to the LPS-induced interferon response and were not observed following activation of viral nucleic acid sensing pathways. Comparison of responses at birth versus age 5 demonstrated that LPS-induced interferon responses but not responses triggered by viral nucleic acid sensing pathways may be subject to strong developmental regulation. These data suggest that the risk of sLRI in early life is in part already determined at birth, and additionally that the developmental status of LPS-induced interferon responses may be a key determinant of susceptibility. Our findings provide a rationale for the identification of at-risk infants for early intervention aimed at sLRI prevention and identifies targets which may be relevant for drug development.