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Targeting the mucosal immune system in a mouse model to prevent pregnancy complications following maternal bacterial infection
Scott NM, Lauzon-Joset JF, Mincham KT, Prescott SL, Robertson SA, Holt PG, Strickland DH
Telethon Kids Institute, The University of Western Australia, Perth Australia
Robinson Institute, University of Adelaide, South Australia.
Maternal exposure to microbial pathogens during pregnancy is frequently associated with exaggerated inflammatory responses and accompanying high intensity acute symptoms, and in some cases more profound follow-on effects ranging from the extreme of premature termination of pregnancy, to growth restriction in the offspring. Preterm birth is the single most important health care issue in fetal-maternal medicine, with a high prevalence in Australia and other developed countries. Children born with low for gestational age weight have an increased susceptibility to subsequent development of a range of persistent diseases, exemplified by atopic asthma. Safe effective treatments that can be used to protect against infection-induced complications would provide exciting new opportunities for improving maternal, fetal and neonatal health. We have developed preclinical mouse models to study mechanisms underlying infection induced pregnancy complications. Recent studies in our lab have demonstrated for the first time that premature pregnancy termination and/or fetal weight loss in response to maternal microbial infection is potentially preventable. We investigated if OM85, a bacterial-derived immunomodulator already in clinical use to control the intensity and duration of infection-associated inflammatory symptoms in susceptible infants and adults, could be repurposed to protect against the effects of infection-associated inflammation in preclinical pregnancy models. Our initial studies with this agent in pregnant mice have involved exposure to bacterial LPS or live influenza virus, and these have demonstrated that OM85 treatment reduces both maternal and fetal susceptibility to the effects of infection-associated inflammatory stress by subtle attenuation of proinflammatory effector pathways exemplified by those driven by TNFa/IL-1, without blunting the capacity of the maternal innate immune system for pathogen eradication. We have demonstrated that a central component of OM-mediated effects in pregnant animals involves fine-tuning of the functions of both innate and adaptive immune cell populations present in maternal gestational tissues. The maintenance of immunological homeostasis at the fetomaternal interface is recognized to be of crucial importance in relation to preservation of normal fetal growth and development, and these proof-of-concept findings with OM85 point towards new therapeutic approaches to protection-of-pregnancy. While our findings to date are unique and conceptually exciting, we will follow up with a more detailed understanding of the precise mechanism-of-action of OM85 in maternal and fetal tissues in experimental infection models as the next step in progression towards human studies in pregnancy with OM85 itself, or a better defined derivative therapeutic.
Plain language summary: During pregnancy, bacterial and viral infection of the mother can cause significant problems to the health of the growing fetus, including loss of life, early delivery and low birth weight. This study has identified how cells within the reproductive tissues respond to maternal bacterial infection during pregnancy to induce these complications, and how this is potentially preventable. This work is the first step to develop safe treatments for use in pregnant mothers to protect against preterm delivery and low birth weight caused by maternal infections.
Funder: National Health and Medical Research Council of Australia