Molecular Dissection of England's Scarlet Fever Upsurge 2015-2016 and Impact on Invasive Infections

The bacterium Group A streptococcus causes a variety of infections, from 'strep sore throat' to more serious internal and bloodstream infections. Strep infections of the throat provide the main supply or 'reservoir' of strep bacteria in the community. Strep bacteria can be transmitted between people's throats in droplets, but, in rare circumstances, the strep bacteria can enter the deeper tissues via a small cut, for example, or can be inhaled into the lungs. Once the bacterium enters deeper parts of the body, it can rapidly overcome the body's immune defences to cause internal and bloodstream (invasive) infections. Although rare, about 2000 people per year acquire these more serious invasive infections in England, a fifth of whom will die.

'Strep throat' occurs throughout childhood, leading to gradually increasing immunity to the more than 100 different families of Group A strep. In young children (4-5 years), strep throat can be complicated by scarlet fever, which is a largely benign condition characterized by a strep throat, red rash and high fever, that is triggered by scarlet fever toxins produced by Group A strep. The risk of scarlet fever (as a complication of strep throat) subsides rapidly after the age of 5 or 6 - probably because children become immune to the toxins - although they still remain at risk of strep throat for many years.

In the UK, we monitor rates of invasive Group A strep, as well as scarlet fever. In keeping with the idea that strep throat infections act as a 'reservoir' for invasive infections, rates of scarlet fever and rates of invasive strep infections tend to follow one another closely. It was therefore alarming when, in Spring 2014, England experienced a surge in scarlet fever cases that was wholly unexpected; roughly ten times the expected number of cases were reported. In 2015 and 2016, the same pattern was repeated. It is possible that a number of factors interacted to create a situation where intense transmission of group A strep occurred among the age group most at risk of scarlet fever; these include reduced GP visits for childhood sore throat, reduced use of throat swab tests, reduced antibiotic prescriptions, and more small children at nursery or in daycare. Scientists considered the possibility that a new strain of group A strep might be to blame, however testing of strains in 2014 did not support this; several strains seemed to be circulating and, fortunately, there was not an increase in invasive infections.

The objective of this project is to understand what has happened subsequently. In 2015 - 2016, the increase in scarlet fever was accompanied by a clear increase in the more dangerous invasive type of group A strep infection. Furthermore, one particular strain has begun to dominate the reservoir of throat infections, including scarlet fever, and we are concerned that this strain might be particularly good at spreading in the community, and might also be better suited to causing invasive infections. The strain has acquired genetic changes that we have not seen previously. The aim of this project is to find out if the new strain type is better at causing throat infections, better at spreading, or can more easily lead to invasive infections. We will test this using a range of laboratory models including human tonsil tissue cultures. We will then undertake genetic studies to change the genes that might be causing the strain to be so successful, to find out which genes are responsible. This is important as we will be able to monitor strains with these changes in future. If we show that the new strain is inherently better suited to causing disease in the community, and that the strain is causing an increase in invasive infections as well as scarlet fever, there will be a basis to propose changes to sore throat management, for example, altering guidance to GPs about treating smaller children with sore throat promptly, or using more diagnostic tests.

Background: Surges of scarlet fever have historically been associated with increased invasive group A streptococcal (iGAS) infection. Major surges of scarlet fever were reported in 2014-2016. Although no increase in iGAS was detected in 2014, in 2016, rates of iGAS rose markedly during the peak weeks of scarlet fever activity. In contrast to 2014, one dominant lineage of GAS emerged in 2015 among throat isolates. This type of GAS was also the leading cause of invasive disease, strongly suggesting that the two events were linked.
Aims: We will determine if the emergent lineage is better suited to causing outbreaks of pharyngeal infections or iGAS, and determine if differences observed could be linked to the specific genetic changes that distinguish this lineage from other strains.

Scientific approach: Genome-sequenced strains representative of the emergent lineage and those that are closely related but not within the emergent lineage will be subject to the following comparisons

A. Fitness to cause nasopharyngeal infection
1. Adhesion to matrix proteins and human tonsil
2. Survival in the mucosal environment
3. Expression of virulence factors associated with pharyngeal infection.
4. Transcriptomic differences on human tonsil.
5. Longevity of carriage in the nasopharynx and transmission

B. Fitness to cause invasive infection or adverse outcome
1. Surviving human immune responses
2. Surviving during soft tissue infection
3. Linkage of iGAS genomic data to demographic, severity, and mortality data.
4. Genomic analysis of throat and iGAS strains to determine similarity.

C. What is the molecular basis for differences in lineage success?
1. Can mutation of the SNP that distinguish the lineage alter its phenotype and reduce fitness?
2. Can introduction of the same SNP to other strains confer increased fitness?

The work will provide definitive information about the new lineage and data regarding the variant genes identified therein

Early in the course of this work, the first beneficiaries will be the academic teams who will gain from the increased investment in their research while the relevant institutions will benefit from the esteem that accompanies such research, including the benefits of publishing research findings in prominent scientific journals. The academics may also benefit from the interest that their work may generate, in terms of opportunities to seek further funding, Fellowship opportunities for the PDRA, and the opportunity to speak at international scientific conferences and, potentially, to members of the public, or the media.

If a new lineage of group A streptococcus can be distinguished from other similar streptococci of the same family using a molecular (PCR) test that is cheaper and quicker than whole genome sequencing, then this could be extended from the research setting to the reference laboratory in order to enhance surveillance for the lineage. Likewise there could be similar benefit for those working in reference laboratories in other countries who wish to undertake surveillance for this lineage, as whole genome sequencing of isolates may not be possible in some locations.

Once data begin to appear from the work, those working in the field of public health policy will be directly affected, since the findings may suggest that interventions are required to limit spread of scarlet fever type illness or other streptococcal infections. The advisors and policy makers will benefit from timely information about the types of strain circulating and will be able to make informed choices about what interventions, if any, are required.

If there is a change to guidance on management of strep throat or scarlet fever, then this will impact on primary care physicians as well as patients who may need to take small children with sore throats to the GP in order to have testing and treatment if necessary for strep throat or scarlet fever. Ultimately the public, especially those with children, are the main beneficiaries since the object of the work is to reduce the risk of invasive strep infection through better understanding of the reservoir of community infection.