Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response

Denise Chan,Malko Adan,Samit Kundu,Marina Botto,Jane E Norman,Lynne Sykes,Belen Gimeno-Molina,Yun S Lee,Richard G Brown,Phillip R Bennett,Sarah J Stock,Pascale Kropf,David A Macintyre,Holly V Lewis,Vasso Terzidou,Saqa Ahmed,Anna L David,T G Teoh

doi:10.1038/s41467-022-28620-1

Abstract

There has been a surge in studies implicating a role of vaginal microbiota in spontaneous preterm birth (sPTB), but most are associative without mechanistic insight. Here we show a comprehensive approach to understand the causative factors of preterm birth, based on the integration of longitudinal vaginal microbiota and cervicovaginal fluid (CVF) immunophenotype data collected from 133 women at high-risk of sPTB. We show that vaginal depletion of Lactobacillus species and high bacterial diversity leads to increased mannose binding lectin (MBL), IgM, IgG, C3b, C5, IL-8, IL-6 and IL-1β and to increased risk of sPTB. Cervical shortening, which often precedes preterm birth, is associated with Lactobacillus iners and elevated levels of IgM, C3b, C5, C5a and IL-6. These data demonstrate a role for the complement system in microbial-driven sPTB and provide a scientific rationale for the development of live biotherapeutics and complement therapeutics to prevent sPTB.

Highlights

There has been a surge in studies implicating a role of vaginal microbiota in spontaneous preterm birth, but most are associative without mechanistic insight
We demonstrate that immune activation and a dysregulated immune response involving the lectin mediated pathway, IgM/IgG complex activated classical pathway, and a pro-inflammatory cytokine milieu occurs in microbial-driven spontaneous preterm birth (sPTB)
Our study identifies cross-talk between the host innate and adaptive immune response in microbial-driven cervical shortening and sPTB

Summary

Introduction

There has been a surge in studies implicating a role of vaginal microbiota in spontaneous preterm birth (sPTB), but most are associative without mechanistic insight. Cervical shortening, which often precedes preterm birth, is associated with Lactobacillus iners and elevated levels of IgM, C3b, C5, C5a and IL-6 These data demonstrate a role for the complement system in microbial-driven sPTB and provide a scientific rationale for the development of live biotherapeutics and complement therapeutics to prevent sPTB. There have been limited advances in prediction, prevention, and treatment of spontaneous preterm birth (sPTB) over the last few decades This is predominantly because it may be due to one of, or a combination of, multiple aetiological factors, yet research studies exploring pathophysiology or therapeutics typically fail to attempt to phenotype cases. Lactobacillus depleted, and high diversity vaginal microbiota are associated with an increased risk of PPROM and of sPTB13–17. The wider implications of these results support the potential for therapeutic modulation of local microbial composition and the immune milieu for the prevention of sPTB

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Conclusion