Unlocking the Mechanisms that Group B Streptococcus uses to Cause Adult Infections

Infections by the bacterium Streptococcus agalactiae, also known as Group B Streptococcus (GBS), have emerged as a major cause of adult invasive across the world. This includes skin and bloodstream infections. Even though GBS has an important clinical historical association with infant diseases, GBS now causes more diseases in adults than in infants in the UK and in many other countries.

The molecular basis and infection processes of these diseases, as well as the similarity or dissimilarity of GBS strains causing infant and adult pathologies, remain to be determined. Alarmingly, the impact of adult GBS infections is expected to continue to grow given the ageing global population and the emergence of antimicrobial resistance in GBS.

To address this global public health problem, we need better detection, surveillance, prevention and treatment options for adult invasive (i)GBS. Crucial to these developments is recognising the primary host-pathogen interactions that GBS uses to initiate invasive adult infections. However, we do not understand these critical mechanisms, as research to date has characterised infant GBS strains and infections.

Our recent work has identified that GBS binds to a human immune receptor called CEACAM1. This is achieved when GBS express a specific protein at their surface called an adhesin. Notably, GBS stains that infect adults, but not infants, commonly express 1 of 3 adhesins that bind CEACAM1.

The human CEACAM1 receptor is an inhibitory immune receptor that is commonly expressed on epithelial cells and leukocytes. It can be targeted by pathogens to hijack inhibitory signalling, suppress immune responses and promote infection. We have clear and convincing preliminary evidence that GBS and CEACAM1 interactions allow GBS to adhere to cells and subvert immune defences.

Thus, we hypothesise that GBS cause invasive diseases in adults by binding to CEACAM1 to subvert immune responses.

This project aims to characterise the biological functions of the GBS and human CEACAM1 receptor interactions. Our objectives are to: -

Determine how adhesin binding to CEACAM1 reduces epithelial and phagocyte defences. We will also detail the impact of natural CEACAM1 variation in these processes, as this not only influences the affinity of the interaction with GBS but likely contributes to susceptibility to infection. Here, we will use epithelial and phagocyte cell infection models to determine how adhesin-CEACAM1 interactions enhance the capacity of GBS to evade immune responses.

Define the effect of CEACAM1 binding by GBS on human intracellular signalling. We will use in vitro and biochemical approaches to define how CEACAM1 binding by GBS influences immune signalling.

Explore how the expression of CEACAM1-binding adhesins promotes the invasion of skin tissue by GBS. To do this, we will infect human skin explants and use microscopy and immunology approaches.

We will generate knowledge at the system level about how CEACAM1 engagement by certain GBS clones drives infection in adults, expanding our fundamental knowledge of these highly invasive life-threatening infections. This will allow better detection, surveillance, preventation or treatment long-term. By shedding light on the intricate system-level interplay, we are not just deepening our knowledge of GBS infections but opening new avenues in immunology.

This has the power to reshape our understanding of inhibitory receptors, presenting opportunities for novel insights and applications in the broader field. The project will provide interdisciplinary training in genetics, biochemistry, cellular models, tissue models and infection biology.