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

A组链球菌可引起多种感染，从“链球菌咽喉痛”到更严重的内部和血液感染。咽喉部的链球菌感染是社区中链球菌的主要来源或“储存库”。链球菌可以在人的喉咙之间以飞沫的形式传播，但在极少数情况下，链球菌可以通过小伤口进入更深的组织，或者可以被吸入肺部。一旦细菌进入身体的更深部位，它可以迅速克服身体的免疫防御，导致内部和血液(侵入性)感染。虽然罕见，但在英国，每年约有2000人感染这种更严重的侵袭性感染，其中五分之一会死亡。链球菌性咽喉炎发生在整个儿童时期，导致对A组链球菌的100多个不同家庭的免疫力逐渐增强。在幼儿(4-5岁)中，链球菌性咽喉炎可能会并发猩红热，这是一种基本上良性的疾病，其特征是链球菌性咽喉、红疹和高烧，由A组链球菌产生的猩红热毒素引发。猩红热(作为链球菌性咽喉炎的一种并发症)的风险在5或6岁后迅速消退--可能是因为儿童对毒素产生了免疫力--尽管他们多年来仍有患链球菌性咽喉炎的风险。在英国，我们监测侵袭性A组链球菌和猩红热的发病率。与链球菌咽喉感染是侵袭性感染的“蓄水池”这一观点一致，猩红热的发病率和侵袭性链球菌感染率往往是密切相关的。因此，令人震惊的是，2014年春季，英国经历了完全出乎意料的猩红热病例激增；报告的病例数量大约是预期数量的十倍。2015年和2016年，同样的模式重演。可能有多种因素相互作用，导致A组链球菌在猩红热风险最高的年龄组中发生剧烈传播；其中包括因儿童喉咙痛而减少到全科医生就诊，减少喉咙拭子检测的使用，减少抗生素处方，以及更多幼儿在托儿所或日托所。科学家们考虑了A群链球菌的一种新菌株可能是罪魁祸首的可能性，但2014年的菌株检测并不支持这一点；几种菌株似乎在传播，幸运的是，侵袭性感染没有增加。这个项目的目标是了解随后发生的事情。在2015-2016年间，猩红热的增加伴随着更危险的侵袭性A群链球菌感染的明显增加。此外，一种特殊的菌株已经开始控制喉部感染的宿主，包括猩红热，我们担心这种菌株可能特别善于在社区中传播，也可能更适合引起侵入性感染。该菌株获得了我们以前从未见过的基因变化。这个项目的目的是找出新的毒株类型是更容易引起喉咙感染，更容易传播，还是更容易导致侵入性感染。我们将使用包括人类扁桃体组织培养在内的一系列实验室模型来测试这一点。然后，我们将进行遗传学研究，以改变可能导致菌株如此成功的基因，找出哪些基因是罪魁祸首。这一点很重要，因为我们将能够在未来监测这些变化的菌株。如果我们证明新的菌株天生更适合在社区中引发疾病，并且这种菌株正在导致侵袭性感染和猩红热的增加，那么就有基础提出改变喉咙痛的治疗方法，例如，改变全科医生关于迅速治疗喉咙痛的年幼儿童的指南，或者使用更多的诊断测试。

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.