i) Intrauterine infection accounts for at least 40% of cases of spontaneous preterm birth. The most common route of pathogen entry into the uterus is likely to be ascent of vaginal microbes as a result of compromised cervico-vaginal innate immune defences. The cervix has a special role in pregnancy; it protects the baby and the uterus from infection. The mucosal surface of the cervix is protected by mucus barriers formed by gel-forming mucus proteins. Our key goal is to investigate the specific role of cervical mucus proteins using genetic knock out mouse models, whilst mimicking preterm birth with bacteria associated with preterm birth in humans (e.g. Gardnerella vaginalis and Prevotella bivia). This work will contribute to further understanding of why preterm birth occurs.
ii) This project will address the hypothesis that a compromised mucus barrier function confers an increased risk of infection-related preterm birth. The student will investigate how in mice that are deficient in certain cervical mucus proteins, this affects their ability to protect against bacteria which are related to preterm birth. A secondary aim will be to assess how these bacteria specifically effect the mother and baby.
iii) The student will acquire animal research skills including breeding, time-mating, genotyping, preterm birth modelling and pregnancy ultrasound. Also general laboratory skills: bacterial culture, immunohistochemistry, immune cell flow cytometry, multiplex ELISAs and qPCR. Statistical and bioinformatic analysis using relevant packages. Other transferrable skills/training and conference attendance.
iv) Years 1 and 2- establish knock out mouse colony, develop preterm infection models using bacteria and determine pregnancy outcomes (including gestation length, pup survival, pup numbers and weights)
Year 3- assess maternal, fetal and neonatal inflammatory profiles in preterm infection model and understand the effects of the cervical mucus proteins on the ability of the cervical barrier to protect from infection.
Cervical mucins and host-defense: fundamental protection against ascending infection and risk of preterm birth
Representative Publications
1. Ascending Vaginal Infection Using Bioluminescent Bacteria Evokes Intrauterine Inflammation, Preterm Birth, and Neonatal Brain Injury in Pregnant Mice. Suff N, Karda R, Diaz JA, Ng J, Baruteau J, Perocheau D, Tangney M, Taylor PW, Peebles D, Buckley SMK, Waddington SN. American Journal of Pathology. 2018.188:2164-2176. doi: 10.1016/j.ajpath.2018.06.016. 2. Cervical gene delivery of Human β-defensin 3 in a mouse model of ascending infection-related preterm birth. Suff N, Karda R, Diaz JA, Ng J, Baruteau J, Perocheau D, Bajaj-Elliott M, Taylor PW, Peebles D, Buckley SMK, Waddington SN. Frontiers in Immunology. 2020. 11:106. doi:10.3389/fimmu.2020.00106. 3. Prior term delivery increases risk of subsequent recurrent preterm birth: An unexpected finding. Suff N, Xu V, Dalla Valle G, Carter J, Brennecke S, Shennan A. Australian and New Zealand Journal of Obstetrics and Gynaecology. 2022. doi:10.1111/ajo.13504.
1. Neutrophils dominate the cervical immune cell population in pregnancy and their transcriptome is modified by the microbial vaginal environment. Mohd Zaki A, Hadingham A, Flaviani F, Haque Y, M J D, Finucane D, DallaValle G, Mason AJ, Saqi M, Gibbons DL, Tribe RM. Front Microbiol. 2022 doi:10.3389/fmicb.2022.904451. 2. Predictive RNA profiles for early and very early spontaneous preterm birth. Camunas-Soler J, Gee EPS, Reddy M, Mi JD, Thao M, Brundage T, Siddiqui F, Hezelgrave N, Shennan AH, Namsaraev E, Haverty C, Jain M, Elovitz MA, Rasmussen M, Tribe RM. AJOG. 2022 doi:10.1016/j.ajog.2022.04.002. 3. Flaviani F, Hezelgrave NL, Kanno T, Prosdocimi EM, Chin-Smith E, Ridout AE, von Maydell DK, Mistry V, Wade WG, Shennan AH, Dimitrakopoulou K, Seed PT, Mason AJ, Tribe RM. Cervicovaginal microbiota and metabolome predict preterm birth risk in an ethnically diverse cohort. JCI Insight. 2021 6: e149257. doi: 10.1172/jci.insight.149257.