Streptococcus pyogenes interaction with the lymphatic hyaluronan receptor LYVE-1 as a mechanism for lymphatic dissemination and disease progression

化脓性链球菌，通常被称为“A组链球菌”，通常会引起喉咙痛、扁桃体炎和脓疱疮等感染，通常发生在儿童身上。然而，它也可以在人与人之间迅速传播，引起危及生命的感染，如坏死性筋膜炎、产妇败血症和中毒性休克，最常见于那些原本健康的人。当从血液中生长时，最致命或最危险的A组链球菌通常表现出一层厚厚的胶囊或外层涂层。严重包封的A组链球菌菌株也与免疫紊乱、风湿热的爆发有关，风湿热是世界范围内心脏瓣膜病的主要原因。再加上与致命性侵袭性链球菌感染的相关性，了解a组链球菌与免疫系统的相互作用，特别是胶囊的作用，是一个重要的必要条件。A族链球菌胶囊是由一种被称为透明质酸或透明质酸的物质制成的，这种大糖被认为能促进伤口愈合、免疫细胞迁移和癌症扩散。我们身体的大部分都充满了透明质酸，A族链球菌可能会利用这种胶囊来掩盖自己的免疫系统。淋巴管是分布在全身的通道，淋巴液流经淋巴腺，带着免疫反应所需的特殊白细胞和透明质酸，透明质酸本身在淋巴结中被分解。淋巴通道内的细胞实际上有一个受体或“钩子”供透明质酸附着，这可能有助于透明质酸进入淋巴通道，尽管人们对透明质酸如何沿着淋巴通道移动知之甚少。我们认为，A组链球菌利用与淋巴管内壁细胞相同的透明质酸“钩子”进入淋巴管并到达淋巴腺。淋巴腺是“仓库”，由身体其他部位感染产生的微生物被传递到这里，这样它们就可以展示给免疫系统，产生保护性免疫反应。我们怀疑A组链球菌透明质酸胶囊不仅帮助微生物到达淋巴结，而且保护它不被免疫系统识别和杀死。在这个项目中，我们将发现A组链球菌是否使用这个系统到达淋巴腺，以及这是否会对感染患者产生不良后果，包括扁桃体炎患者和那些更危险的感染，如坏死性筋膜炎患者。在提议的工作中，我们将测试目前在英国引起疾病的菌株在淋巴管中被贩运的能力，以及在实验室中被改变以表达或多或少量胶囊的菌株。如果我们能够证明a组链球菌与淋巴细胞相互作用的有害作用，那么就有可能阻断或阻止淋巴细胞与链球菌之间的相互作用，并开发出防止侵袭性感染进展或防止引发炎症的治疗方法。

Streptococcus pyogenes, often known as 'group A strep' normally causes infections such as sore throat, tonsillitis and impetigo, commonly among children. However, it can also spread from person to person rapidly, to cause life-threatening infections such as necrotising fasciitis, maternal sepsis, and toxic shock, most commonly in those who were otherwise previously fit and healthy. The most virulent, or dangerous, types of group A strep often demonstrate a thick capsule, or outer coating, when grown from the blood stream. Heavily encapsulated strains of group A strep have also been associated with outbreaks of the immune disorder, rheumatic fever, the leading cause of valvular heart disease worldwide. Coupled with the relevance to lethal invasive strep infections, there is a major imperative to understand the interaction of group A strep with the immune system focussing in particular on the role of the capsule. The group A strep capsule is made from a substance known as hyaluronic acid or hyaluronan, a large sugar thought to facilitate wound healing, immune cell migration and cancer spread. Much of our own body is filled with hyaluronan, and group A strep may use this capsule to cloak itself from our immune system. Lymphatics are channels distributed throughout the body, through which fluid known as lymph flows to lymph glands, taking with it, the specialised white blood cells required for immune responses and also, hyaluronic acid - which is itself broken down in lymph nodes. The cells lining lymphatic channels actually have a receptor or 'hook' for hyaluronan to latch onto, presumably helping the hyaluronic acid to enter the channel although little is known about how the hyaluronan moves along the channels. We believe that group A strep exploits the very same hyaluronan 'hook' on the cells lining the lymphatic channel in order to enter lymphatics and reach lymph glands. The lymph glands are "depots" where microbes arising from infections elsewhere in the body are conveyed, so that they can be exhibited to the immune system to generate a protective immune response. We suspect that the group A strep hyaluronan capsule not only helps the microorganism to get to the lymph nodes but also protects it from being recognised and killed by the immune system. In this project we will find out whether group A strep does use this system to reach the lymph glands, and whether that has adverse consequences for people with infection, both those with tonsillitis and those with more dangerous infections such as necrotising fasciitis. In the work proposed, we will test strains that are currently causing disease in the UK for their ability to be trafficked in lymphatics, as well as strains that have been altered in the laboratory to express greater or lesser amounts of capsule. If we were able to show a deleterious effect of group A strep interacting with lymphatics, it might then be possible to block or prevent the interaction between the lymphatic cells and the streptococcus from occurring, and to develop treatments to prevent invasive infections from progressing, or to prevent triggering of inflammation.