The molecular foundation of cervical mucus plug protection from intrauterine infection during pregnancy

During pregnancy, the cervix undergoes dramatic remodelling characterised by the emergence of mucus secreting goblet cells (GCs) that generate a cervical mucus plug (CMP) in the cervical canal.

The CMP is thought to act as a barrier that is crucial for maintaining uterine sterility, thereby protecting the foetus from ascending bacterial infections.

However, this view is based on relatively little experimental evidence and our knowledge of specific endogenous or exogenous factors that may regulate cervical GC functions and CMP properties is virtually non-existent.

This knowledge gap has significant clinical implications, as preterm birth is a common consequence of intrauterine bacterial infections and is associated with up to 0.6 million annual infant deaths.Over the previous decade, significant research efforts have been made to dissect GC and mucus protective functions in the gut and lungs, while the female reproductive tract has been largely neglected.

Fortuitously, much of the knowledge and tools developed by this research can be repurposed to study cervical GCs and the CMP.

These include transgenic mice with tagged cervical GCs, null mutant mouse models, targeted mucus biochemical and barrier property analytics, ex vivo mucosal methodologies and large-scale mutagenesis libraries of bacteria that can cause intrauterine infection.In this proposal we will repurpose these tools to: 1) Define GC and CMP gestational dynamics in pre-clinal mouse models; 2) Identify causal links between endogenous and exogenous factors that regulate GC and CMP functions; 3) Screen for bacterial virulence factors associated with breach of the CMP during pregnancy; 4) Isolate CMP alterations associated with human preterm birth.

Addressing these aims will provide new insights into GC and mucus biology, host-pathogen interactions and develop a deeper understanding of female reproductive biology that can applied to the development of precision interventions to reduce infant mortality