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

2015-2016 年英国猩红热热潮的分子剖析及其对侵袭性感染的影响

• 批准号: MR/P022669/1
• 负责人: Shiranee Sriskandan
• 金额: $ 52.96万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP022669%2F1
• 关键词: Molecular; Dissection; England; Scarlet; Fever

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.

A组链球菌会引起各种感染，从“链球菌性咽喉炎”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供应或“储存库”。链球菌可以通过飞沫在人的喉咙之间传播，但是在极少数情况下，链球菌可以通过小切口进入更深的组织，例如，或者可以吸入肺部。一旦细菌进入身体更深的部位，它可以迅速克服身体的免疫防御，引起内部和血液（侵入性）感染。虽然罕见，但在英国每年约有2000人获得这些更严重的侵入性感染，其中五分之一将死亡。“链球菌性咽喉炎”发生在整个儿童时期，导致对A组链球菌100多个不同家族的免疫力逐渐增加。在幼儿（4-5岁）中，链球菌性咽喉炎可并发猩红热，这是一种基本上良性的疾病，其特征是链球菌性咽喉炎，红色皮疹和高烧，由A组链球菌产生的猩红热毒素引发。猩红热（作为链球菌咽喉的并发症）的风险在5岁或6岁后迅速消退-可能是因为儿童对毒素产生免疫力-尽管他们多年来仍然存在链球菌咽喉的风险。在英国，我们监测侵袭性A组链球菌和猩红热的发病率。与链球菌咽喉感染作为侵入性感染的“水库”的想法一致，猩红热的发病率和侵入性链球菌感染的发病率往往密切相关。因此，2014年春季，英格兰的猩红热病例激增，这是完全出乎意料的;报告的病例数量大约是预期的十倍。在2015年和2016年，同样的模式重复出现。许多因素可能相互作用，造成A组链球菌在猩红热风险最高的年龄组中发生强烈传播的情况;其中包括减少儿童喉咙痛的全科医生就诊、减少喉咙拭子测试的使用、减少抗生素处方以及托儿所或日托中心的幼儿数量增加。科学家们认为可能是一种新的A组链球菌菌株造成的，但2014年的菌株测试并不支持这一点;几种菌株似乎正在传播，幸运的是，侵入性感染并没有增加。这个项目的目的是了解后来发生了什么。在2015 - 2016年，猩红热的增加伴随着更危险的侵袭型A组链球菌感染的明显增加。此外，有一种特别的病毒株已开始在包括猩红热在内的咽喉感染宿主中占主导地位，我们担心这种病毒株可能特别善于在社区中传播，也可能更适合造成侵入性感染。该菌株已经获得了我们以前从未见过的遗传变化。该项目的目的是找出新的菌株类型是否更容易引起咽喉感染，更容易传播，或者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，我们将进行基因研究，改变可能导致菌株如此成功的基因，以找出哪些基因负责。这一点很重要，因为我们将来将能够监测这些变化的菌株。如果我们证明新菌株本质上更适合在社区中引起疾病，并且该菌株正在导致侵入性感染和猩红热的增加，那么将有一个基础来建议改变喉咙痛管理，例如，改变全科医生关于及时治疗喉咙痛的较小儿童的指导，或者使用更多的诊断测试。

项目成果

Clinical management and impact of scarlet fever in the modern era: findings from a cross-sectional study of cases in London, 2018-2019

现代猩红热的临床管理和影响：2018-2019 年伦敦病例横断面研究的结果

• DOI: 10.1101/2021.06.25.21259535
• 发表时间: 2021
• 作者: Herdman M

Clinical management and impact of scarlet fever in the modern era: findings from a cross-sectional study of cases in London, 2018-2019.

• DOI: 10.1136/bmjopen-2021-057772
• 发表时间: 2021-12-24
• 期刊: BMJ OPEN
• 影响因子: 2.9
• 作者: Herdman, Michael Trent;Cordery, Rebecca;Karo, Basel;Purba, Amrit Kaur;Begum, Lipi;Lamagni, Theresa;Kee, Chuin;Balasegaram, Sooria;Sriskandan, Shiranee
• 通讯作者: Sriskandan, Shiranee

Characterisation of emergent toxigenic M1 UK Streptococcus pyogenes and associated sublineages

新兴产毒 M1 UK 化脓性链球菌及相关亚系的特征

• DOI: 10.1101/2022.12.27.522030
• 发表时间: 2022
• 作者: Li H

Frequency of transmission, asymptomatic shedding, and airborne spread of Streptococcus pyogenes in schoolchildren exposed to scarlet fever: a prospective, longitudinal, multicohort, molecular epidemiological, contact-tracing study in England, UK.

• DOI: 10.1016/s2666-5247(21)00332-3
• 发表时间: 2022-05
• 期刊: LANCET MICROBE
• 影响因子: 38.2
• 作者: Cordery, Rebecca;Purba, Amrit K.;Begum, Lipi;Mills, Ewurabena;Mosavie, Mia;Vieira, Ana;Jauneikaite, Elita;Leung, Rhoda C. Y.;Siggins, Matthew K.;Ready, Derren;Hoffman, Peter;Lamagni, Theresa;Sriskandan, Shiranee
• 通讯作者: Sriskandan, Shiranee

Frequency of transmission, asymptomatic shedding, and airborne spread of Streptococcus pyogenes among schoolchildren exposed to scarlet fever: a longitudinal multi-cohort molecular epidemiology contact tracing study

接触猩红热的学童中化脓性链球菌的传播频率、无症状脱落和空气传播：一项纵向多队列分子流行病学接触追踪研究

• DOI: 10.1101/2021.07.04.21259990
• 发表时间: 2021
• 作者: Cordery R