A child’s genetic code may determine why a common sore-throat bacterium turns deadly in some children but not others. Strep A infections cause mild illness in most children, but a small number develop life-threatening disease that can destroy tissue or damage the heart and kidneys. The recent surge in severe cases—children now account for 24 percent of serious infections, up from 4–12 percent—has made the question “Why my child?” urgent for families and clinicians. Current science cannot explain why some children are hit so hard. This project will search for genetic variants that make children vulnerable to severe Strep A. The researcher has already identified a gene region involved in sugar transport that affects immune responses. By studying children affected during the recent upsurge, and testing how gene differences alter immune cells and skin models, the work aims to turn a statistical genetic link into a biological explanation. If successful, this fundamental science could reveal targets for future treatments. It will not change care immediately, but understanding the mechanism is the first step toward therapies that prevent the infection from turning catastrophic.
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'Strep A' infections usually cause sore throat and relatively minor illness but sometimes can invade deeper normally sterile parts of the body often entering through the skin or lungs, leading to life-threatening illness. Immune responses to the same bacteria can also do long-term harm to the heart and kidneys, which still pose significant health risks in less affluent regions of the world. Over the past year, there has been a concerning increase of severe Strep A infections in Europe (including the UK) and North America. Whilst this rise has affected all age groups, it has been a particular concern in children since they accounted for 24 percent of serious Strep A infections, compared with 4 to 12 percent in previous years (1). It is very likely that these increases reflect changes in population immunity due to social-distancing restrictions during the COVID-19 pandemic, but this does not explain why some children were affected so severely. Challenge: Consequently, in this proposed research project I will aim to answer: "Why are some children more prone to severe Strep A infection than others?" In preparation for this project, I have spoken to the two major patient groups for Strep A infections in the UK: the Lee Spark Foundation and the Conor Kerin Foundation. Both groups emphasised the importance of this question to those affected and their families. This was also reflected in the survey for parents from the NIHR Imperial Biomedical Research Centre in 2021 which found that answering "Why my child?" was a priority area of future research for families (2). Objectives: Therefore, my project will investigate how a child's genetic make-up puts them at risk of severe Strep A infection. Work by my proposed supervisor that I have recently helped extend found specific genetic differences that predispose to life-threatening Strep A infection in both children and adults. These differences are found in the region of a gene involved in transport of sugar molecules needed for a variety of biological processes and known to impact immune responses (3). With the support of this fellowship, I aim to: Refine the link between this gene region and life-threatening Strep A infection including looking at further children affected during the recent upsurge; Investigate how differences between individuals in this gene region alters responses to the bacteria looking at cells and laboratory models of skin. Additionally, I will gain training to analyse the remainder of the genetic code from affected children giving me the opportunity to identify further genetic culprits predisposing to Strep A. Applications: My project will start to provide an answer to "Why my child?". Importantly, it has the potential to bridge-the-gap from a statistical link between a gene and severe infection to understanding what goes wrong in the body that allows the bacteria to take hold. This has potential for clinical application, especially providing targets for future treatments. Thus, this project is not only focused on advancing our understanding but also improving the outcomes for children who develop these devastating infections.
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