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

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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.