New research by Snyder Institute investigators Laura Sycuro, Karen Lithgow and their research team uncovers promising therapeutic targets to prevent infection-induced preterm birth

Preterm birth affects 8% of pregnancies in Canada and is a leading cause of infant and child mortality worldwide. Although preterm births have many different causes, up to 60% of spontaneous preterm labour cases arise from bacterial infection in the uterus. In particular, the presence of bacteria associated with the common vaginal affliction bacterial vaginosis (BV) correlates with increased risk of preterm birth.

The ability of select BV bacteria to reach the uterus and infect pregnancy tissues has been linked to premature rupture of membranes, spontaneous abortion and preterm labour. However, understanding of how these bacteria affect the uterine environment and causally contribute to pregnancy complications is lacking. Extracellular protein degradation (also known as proteolysis) is a central feature of labour induction. It directly remodels pregnancy tissues and regulates pathways leading to cervical dilation, fetal membrane rupture and uterine contractions. Proteolysis that is inappropriately timed can lead to dysregulated signalling cascades and aberrant tissue degradation that initiate premature labour.

In a recent study published in nature partner journals|Biofilms and Microbiomes, a Snyder Institute/UAlberta research team has discovered that preterm birth-associated BV bacteria share a capacity to secrete broad-acting proteolytic enzymes. These enzymes degrade structural components of pregnancy tissues (collagens) and disrupt blood clotting, which is critical for tissue remodeling throughout pregnancy. More specifically, the team identified and experimentally validated the activity of a protease (PepO) secreted by the preterm birth-associated species Porphyromonas asaccharolytica – this represents the first virulence factor described for this species, a urogenital cousin of the oral pathogen Porphyromonas gingivalis, a known cause of gum disease and related blood infections that can lead to preterm birth. (Read the blog here.)

First author Dr. Karen Lithgow, PhD, (Snyder Institute for Chronic Diseases, UCalgary) and a study team led by Dr. Laura Sycuro, PhD (Snyder Institute for Chronic Diseases and Alberta Children’s Hospital Research Institute, UCalgary) confirmed that PepO proteins are capable of degrading cervical collagens and other proteins; moreover, they identified PepO proteases in related bacterial species that have been linked to preterm birth, HIV acquisition and uterine cancer. The research team included Vienna C. H. Buchholz (UCalgary/UAlberta), Emily Ku (UCalgary), Shaelen Konschuh (UCalgary), and Ana D'Aubeterre (UCalgary/UAlberta). 

“This work is important because it expands our understanding of how vaginal bacteria could cause preterm birth,” says Principal Investigator Dr. Sycuro. “To date, the prevalent theory has been that microbiome bacteria trigger the maternal immune response, which in turn activates human labour-inducing proteases. But our data show certain bacterial proteases may disperse through the reproductive tract and directly damage pregnancy tissues.”

Future work aims to understand how these proteases disrupt immune responses and will examine whether bacterial proteases can proteolytically activate labour cascades. Since inhibitors of proteolytic processes can be designed with exquisite specificity, this work could uncover promising therapeutic targets to prevent infection-induced preterm birth.

Sycuro adds, “Further research is needed to determine whether bacterial proteases could independently initiate premature cervical dilation or augment labour induction pathways. However, if this is the case, it would present a unique opportunity to develop new therapies that block bacterial proteins to prevent preterm birth.’

This work was supported by the Canadian Institutes of Health Research, the National Institutes of Health, the Canadian Foundation for Innovation John R. Evans Leaders Fund, Alberta Innovates, the Government of Alberta, the University of Calgary’s Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, the International Microbiome Centre, the O’Brien Centre for the Bachelor of Health Sciences, and the Program for Undergraduate Research Experience.