Molecular basis for transmission of Streptococcus pyogenes

Group A streptococcus (Strep A) is a highly lethal bacterium that can cause not only simple sore throats and skin infections, but also more deadly infections such as bloodstream infection and toxic shock. It is a major cause of severe sepsis in people who are otherwise healthy, which is why its effects often seem so devastating. It can also affect women who have recently given birth causing something known as childbed fever, or puerperal sepsis; although very rare, this sadly can result in deaths.

Strep A only infects humans, which means that infections almost always result from catching the bacteria from another person. It is believed that throat infections are caught from close contact, by mucus from one person reaching another, or by inhaling large droplets spread from another person close by. Skin infections are believed to result from close contact and touch, particularly when the skin is already broken. This is why precautions such as handwashing, and cleaning surfaces are very important when dealing with vulnerable people who may have wounds, or have recently had a baby.

Outbreaks of Strep A occur in hospitals, nurseries, care homes, and prisons; anywhere where people who might be more vulnerable are crowded together. Sometimes these outbreaks carry on, even when precautions like handwashing are being adhered to, or involve people who were never close to one another. This raises the possibility that Strep A might be transmitted in the air, in smaller droplets that can remain in the air for longer than larger droplets.

Scarlet fever is another infection caused by Strep A, that mainly affects small children and is very infectious. Recently, we investigated outbreaks of scarlet fever in schools and found evidence in some classrooms that Strep A was indeed present in the air. Many of the otherwise healthy children in the classroom had the same strain of Strep A in their throats, and some were able to cough it out. This means that some outbreaks may indeed be associated with airborne Strep A, and to stop those outbreaks, it may sometimes be necessary to introduce precautions to reduce airborne spread; handwashing alone may not be sufficient. Precautions might include improved ventilation, reducing room occupancy and wearing of masks, similar to what was done at the start of the March 2020 COVID-19 lockdown. Those interventions had a dramatic dampening effect on scarlet fever outbreaks that, at the time, were increasing rapidly.

We think some strain types are better at spreading in the air than others. In the UK, we have seen new variants of Strep A emerge that, over a period of 4-5 years, have risen to become dominant. This suggests they have a major advantage over older strain types. Similar to viral variants of COVID-19 that were observed to replace older strain types, we believe that the main basis for advantage will be transmissibility .

This project sets out to determine which strains of strep A are most suited to airborne spread and which ones are not, to help public health teams decide how best to deal with an outbreak. The project will also use a technique knowns as TraDIS to try to work out which genes in Strep A allow it to survive in different environments such as 'air', or on different surfaces. This could provide some insight into why bacteria behave differently and might allow us to predict how new clones of bacteria, similar to new variants of COVID19, might behave.

The central hypothesis in this work, is that some strain types of Streptococcus pyogenes may be better-suited to contact-mediated spread and survival on fomites, while others may be better-suited to survival in the air and, therefore, airborne spread. We aim to determine if this is correct, using emm type as a surrogate of genetic similarity, and then to determine the genetic traits required for fitness in airborne survival and fomite survival. We will focus on emergent lineages that are of greatest importance in the UK: The newly emergent and now-dominant emm1 and emm89 lineages that are not only the leading cause of outbreaks in the UK, but also the leading causes of sporadic invasive infections. We will compare these with other leading strains that have also caused outbreaks including those where epidemiological information points to contact-mediated transmission.

Our aims are to-
1. Determine if specific genotypes of S. pyogenes exhibit strain-specific phenotypes with regard to survival in air and on fomites including skin? This will be addressed using laboratory-based techniques and in fieldwork during outbreaks in the community.
2. Create a library of transposon mutants in key outbreak lineages (M1UK , M89UK , and up to one other lineage) that can be used for Transposon directed insertion-site sequencing (TraDIS)
3. Use the libraries to identify genes that are required for fitness to survive airborne dispersal in the three lineages
4. Use the libraries to identify genes that are required for fitness to survive on fomites in the three lineages.
5. Confirm key findings for each strain type using targeted mutagenesis of up to five genes per strain, and then confirm biological relevance of key genes in models of nasal airborne shedding and skin contamination.

Ultimately the findings will inform public health interventions for S. pyogenes outbreaks and build capacity in S. pyogenes transmission biology and examination of newly emergent variants.