bioRxiv preprint doi: https://doi.org/10.1101/057356; this version posted June 7, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. A dormant microbial component in the development of pre-eclampsia1 1,2,3,*Douglas B. Kell & 4,5*Louise C. Kenny 1School of Chemistry, 2The Manchester Institute of Biotechnology, and 3Centre for Synthetic Biology of Fine and Speciality Chemicals, The University of Manchester, 131, Princess St, MANCHESTER M1 7DN, Lancs, UK 44The Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork, Cork, Ireland, and 5Department of Obstetrics and Gynecology, University College Cork, Cork, Ireland A dormant microbial component in the development of pre-eclampsia ......................................................... 1 Abstract ......................................................................................................................................................... 3 Introduction ................................................................................................................................................... 5 Pre-eclampsia ............................................................................................................................................ 5 Heritability ............................................................................................................................................... 10 Inflammation ........................................................................................................................................... 10 Bacterial viability ..................................................................................................................................... 12 Dormancy ................................................................................................................................................ 13 Prevalence of dormant, persistent or latent bacteria in infection microbiology ........................................ 13 Iron and inflammation ............................................................................................................................. 13 Detecting dormant microbes ................................................................................................................... 14 A dormant blood microbiome ................................................................................................................. 15 Direct evidence for a role of infectious agents in PE ................................................................................... 16 Vaginal, placental and amniotic fluid microbiomes in PE ....................................................................... 18 Origins of a blood and tissue microbiome ................................................................................................... 19 Gut origins of blood microbes and LPS .................................................................................................... 19 Pre-eclampsia and periodontal disease .................................................................................................. 19 Urinary tract infections (UTI) ................................................................................................................... 21 From blood to and from the placenta; a role for microparticles ............................................................ 21 Evidence from antibiotic therapies ............................................................................................................. 21 Role of LPS in PE .......................................................................................................................................... 22 Effects of LPS and other microbial antigens on disrupting trophoblast invasion and/or stimulating parturition ................................................................................................................................................... 22 A note on the terminology of sepsis ........................................................................................................... 23 1 Paper 8 in the series “The dormant blood microbiome in chronic, inflammatory diseases” 1 bioRxiv preprint doi: https://doi.org/10.1101/057356; this version posted June 7, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Pre-eclampsia and neonatal sepsis ............................................................................................................. 24 PE biomarkers and infection........................................................................................................................ 24 Proteomic and similar biomarkers – circulating and placental ............................................................... 25 Activin A ............................................................................................................................................... 25 Calretinin ............................................................................................................................................. 25 Chemerin ............................................................................................................................................. 25 Cystatin C ............................................................................................................................................. 25 D-dimer ................................................................................................................................................ 25 Endoglin ............................................................................................................................................... 26 Ferritin ................................................................................................................................................. 26 miRNAs ................................................................................................................................................ 26 Neuropeptide Y .................................................................................................................................... 26 NGAL (lipocalin 2, siderocalin) ............................................................................................................. 26 Placental growth factor (PlGF)............................................................................................................. 27 Procalcitonin ........................................................................................................................................ 27 Serum amyloid A.................................................................................................................................. 27 Soluble fms-like tyrosine kinase-1 (sFlt). ............................................................................................. 27 Thrombomodulin ................................................................................................................................. 27 TLR4 ..................................................................................................................................................... 27 Visfatin ................................................................................................................................................. 27 Metabolomic biomarkers ........................................................................................................................ 28 Noradrenaline (norepinephrine) ......................................................................................................... 29 Uric acid ............................................................................................................................................... 29 Clotting, coagulopathies and fibrinogen in PE ............................................................................................ 29 Prevention Strategies .................................................................................................................................. 30 Coda – a return to the Bradford Hill criteria ............................................................................................... 34 Other predictions ........................................................................................................................................ 34 Concluding remarks ..................................................................................................................................... 35 Acknowledgements ..................................................................................................................................... 35 Legends to Figures ....................................................................................................................................... 36 Legends to Tables ........................................................................................................................................ 37 References ..................................................................................................................................................