Cervical epithelial damage promotes Ureaplasma parvum ascending infection, intrauterine inflammation and preterm birth induction in mice

Ioannis Pavlidis,Ioannis Pavlidis,Ioannis Pavlidis,Gabriella Sammut Demarco,Gabriella Sammut Demarco,Jane E Norman,Heather Macpherson,Gabriella Sammut Demarco,Heather Macpherson,Sarah J Stock,Sarah J Stock,Sarah J Stock,Heather Macpherson,Sarah E M Howie,Sarah E M Howie,Sarah E M Howie,Owen B Spiller

doi:10.1038/s41467-019-14089-y

Abstract

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth.

Highlights

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases
We examine a mouse model of ascending infection following vaginal inoculation by UP, and characterise an increased rate of ascending infection and Preterm birth (PTB) resulting from preinfection cervical exposure to N-9, a commonly used spermicide that has been approved for use by the US Food and Drug Administration
Exposure to 2%, 5% and 10% N-9 resulted in statistically significant increases in pathological score (Fig. 1b; 4.33 ± 0.36, P = 0.0043 for 2%; 3.89 ± 0.29, P = 0.0265 for 5%; and 4.42 ± 0.48, P = 0.0033 for 10%, mean ± standard error of the mean (SEM), Dunnett’s multiple comparisons test) compared to PBS controls (2.083 ± 0.37)

Summary

Introduction

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Downstream intracellular events driven by the transcription factors nuclear factor-κB (NF-κB)[10] and activator protein-1 (AP-1)[11] lead to the increased expression of pro-inflammatory cytokines, among which interleukin-1b (IL-1b)[12], IL-613, IL-814 and tumour necrosis factor-α (TNFα)[15]. Ureaplasma spp. are the most common organisms isolated from amniotic fluid obtained from women who present with the PTB antecedents of preterm labour with intact membranes; preterm premature rupture of membranes (pPROM); short cervix associated with microbial invasion of the amniotic cavity; as well as from infected placentas[27]. It is probable that more than one ‘insult’ is required to potentiate the likelihood of PTB

Methods

Results

Conclusion