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Predicting and preventing spontaneous preterm birth

Supervisors: Professor Nigel Klein, Dr Patricia Hunter and Dr Dagmar Alber

Background:

In the majority of early spontaneous preterm births (SPTB), inflammation in the form of chorioamnionitis is found in the baby’s placenta and membranes on histopathological examination. Molecular detection of bacteria in these tissues has found that SPTB is distinguished by a higher frequency of bacterial colonisation and by the nature and diversity of bacterial species compared to births at term.1,2 While bacteria can infect and sometimes cross the placenta via the maternal circulation, in most cases bacteria access the fetus by ascending the cervical canal and invading the choriodecidual membrane at the point where it covers the cervix.3 The observed chorioamnionitis is thought to be the manifestation of the maternal immune response to bacterial invasion of these tissues. 

In theory, the mucosal immunity of the cervix and vagina should prevent ascending infection. Indeed, we and others have discovered that weak or absent cervical immunity is a risk factor for spontaneous preterm birth.4,5 We have shown that pregnant women who lack antimicrobial components of the cervical mucosa are at increased risk of preterm birth. We hold the patent on this method of assessing cervical immunity and we are developing a diagnostic test that can be used at the start of antenatal care to identify pregnancies at the highest risk of preterm delivery so that steps can be taken to prolong the pregnancy and prevent preterm birth.  

Aims/Objectives:

1. To broaden our understanding of cervical mucosal immunology to incorporate concepts of sexual transmission of HIV, disease course and pathology of sexually transmitted infections (STI), including HPV, Chlamydia and Gonorrhoea. This aim could potentially involve working outside of the UK in areas with high levels of HIV and/or malaria infection.

2. To undertake pre-clinical development of a natural antimicrobial that may be able to enhance cervical immunity and prevent ascending infection in pregnancy.

Methods:

Experiments in the lab of Professor Nigel Klein make use of next generation sequencing and PCR to characterize microbial pathogens and mucosal microbiomes. Immunology is studied using flow cytometry and multiplexed protein detection. Modelling of the interaction between microbes and human cells is done with in vitro culture systems. The incumbent will have the opportunity to develop new in vitro systems.

References:
1.    Jones HE, Harris KA, Azizia M, Bank L, Carpenter B, Hartley JC, Klein N, Peebles D. Differing prevalence and diversity of bacterial species in fetal membranes from very preterm and term labor. PLoS One 2009: 4(12) e8205
2.    de Goffau MC, Lager S, Sovio U, Gaccioli F, Cook E, Peacock SJ, Parkhill J, Charnock-Jones DS, Smith GCS. Human placenta has no microbiome but can contain potential pathogens. Nature 2019; 572(7769):329-334. doi: 10.1038/s41586-019-1451-5. Epub 2019 Jul 31. Erratum in: Nature. 2019 Oct;574(7778):E15. PMID: 31367035; PMCID: PMC6697540.
3.     Al-Adnani M, Sebire N. The role of perinatal pathological examination in subclinical infection in obstetrics. Best Pract Res Clin Obstet Gynaecol 2007; 21(3):505-21.
4.    Hunter P, Sheikh S, David AL, Peebles DM, Klein N. Cervical leukocytes and spontaneous preterm birth. Journal of Reproductive Immunology 2016; 113: 42-49. 
5.    Elovitz MA, Gajer P, Rils V, Brown AG, Humphrys MS, Holm JB, Ravel J. Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery. Nat Commun 2019: 10(1); 1305.