Host genetic susceptibility to life-threatening Streptococcus pyogenes infection in children
Lead Research Organisation:
Imperial College London
Department Name: Infectious Disease
Abstract
'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.
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.
Technical Summary
Group A Streptococcus (GAS) is a bacterium evolved to infect the human host, particularly children. Usually, it causes relatively mild disease, but invasive GAS infection (iGAS) can be catastrophic. My project aims to identify genetic variants in otherwise healthy children which predispose to iGAS infection and elucidate mechanisms of susceptibility.
This is an important project given the rise in iGAS rates worldwide, including the UK in 2022 and 2023. This epidemic disproportionately affected children under the age of ten, with 24 percent of iGAS infections in this group, compared with 4 to 12 percent in previous years. In the UK, the emm1 strain which frequently caused iGAS between 2015 and 2018 returned as the dominant cause of invasive infection in the upsurge, emphasising the importance of host susceptibility. On a population-level the rise was likely to be related to changing patterns of immunity and high rates of viral co-infection, following the easing of physical distancing restrictions after the COVID-19 pandemic. However, on an individual level, it remains unclear why only a minority of children exposed developed life-threatening iGAS infection. Thus, it is hypothesised that these children had a genetic predisposition, which if uncovered is likely to reveal key aspects of iGAS disease mechanisms.
To investigate this, I plan to replicate a recent finding implicating a region of the genome with GAS susceptibility as well as identify other risk variants. I will then study and modify cells of specific genotypes to understand the consequences of these risk variants on expression and wound healing. The project has the potential to advance our understanding of the biological pathways involved in GAS infection, giving much-needed insight into the mechanisms behind GAS pathogenesis and host protection, providing potential targets for drug development.
This is an important project given the rise in iGAS rates worldwide, including the UK in 2022 and 2023. This epidemic disproportionately affected children under the age of ten, with 24 percent of iGAS infections in this group, compared with 4 to 12 percent in previous years. In the UK, the emm1 strain which frequently caused iGAS between 2015 and 2018 returned as the dominant cause of invasive infection in the upsurge, emphasising the importance of host susceptibility. On a population-level the rise was likely to be related to changing patterns of immunity and high rates of viral co-infection, following the easing of physical distancing restrictions after the COVID-19 pandemic. However, on an individual level, it remains unclear why only a minority of children exposed developed life-threatening iGAS infection. Thus, it is hypothesised that these children had a genetic predisposition, which if uncovered is likely to reveal key aspects of iGAS disease mechanisms.
To investigate this, I plan to replicate a recent finding implicating a region of the genome with GAS susceptibility as well as identify other risk variants. I will then study and modify cells of specific genotypes to understand the consequences of these risk variants on expression and wound healing. The project has the potential to advance our understanding of the biological pathways involved in GAS infection, giving much-needed insight into the mechanisms behind GAS pathogenesis and host protection, providing potential targets for drug development.
