A molecular basis for autoimmune sequelae of streptococcal infections

对几乎所有已知抗生素具有耐药性的细菌的出现是科学面临的最重要挑战之一。如果没有新的预防和治疗细菌感染的选择，我们可能很快就会回到19世纪的状态，当时人们死于我们最近认为是微不足道的感染。为了开发与青霉素等药物明显不同的疫苗或治疗方法，我们需要更好地了解细菌引起感染的方式。首先，细菌必须在人体内站稳脚跟。这是通过存在于细菌表面的各种分子实现的。这些分子，主要是通常形成毛发状结构的蛋白质，在身体的各个部位（例如喉咙，肺，内脏，皮肤）与人体组织结合。了解这些表面分子的结构和功能是疫苗开发所必需的。此外，如果有可能防止细菌与宿主结合，就有可能在早期阶段干预感染。链球菌是影响人类和动物的最常见病原体之一。每年有数亿例链球菌性咽喉炎是由化脓性链球菌引起的。到目前为止，在卫生保健良好的国家，青霉素治疗一直有效地控制这种常见的感染。但随着耐药肺炎球菌的突然出现，C.艰难梭菌和耐甲氧西林金黄色葡萄球菌已经表明，我们需要为S。化脓性链球菌在任何时候都会产生青霉素耐药性（许多菌株已经对各种其他药物产生耐药性），这可能会产生毁灭性的后果。例如，如果不治疗/可治疗，链球菌性咽喉炎可能发展成危及生命的疾病，如风湿性心脏病（RHD）。尽管青霉素可用，但RHD是印度和其他发展中国家儿童和青少年的最大杀手之一。在风湿性心脏病中，我们的免疫系统会对抗体内的蛋白质并破坏心脏瓣膜组织。这种破坏性的影响只是知之甚少，但已知与一个蛋白质家族（称为M蛋白）有关，这些蛋白质在显微镜下看起来像一层毛茸茸的外套。M蛋白在80多年前被发现，并很快意识到链球菌需要引起疾病。尽管它们丰富而重要，但我们对它们如何发挥作用的理解非常有限。这种缺乏进展可以用M蛋白的不寻常特性来解释，这使得它们成为常规分子研究的困难对象。我们已经证明，使用互补的强大生物物理技术（NMR和EPR）的组合可以取得重大进展，这些技术将在原子水平上揭示M蛋白的外观以及它们如何工作。在这个项目中，我们将专门研究M蛋白与最丰富的人类蛋白质胶原蛋白的结合。胶原蛋白遍布全身，它的丰富使其成为细菌特别有吸引力的目标，并可能有助于建立感染。重要的是，细菌与胶原蛋白的结合也可能是RHD的根本原因，因为胶原蛋白是心脏瓣膜组织的主要成分。有趣的是，由细菌感染引起的风湿性疾病与常见的自身免疫性疾病（如类风湿性关节炎）之间存在相似之处。类风湿性关节炎的病因尚不清楚，但有人认为细菌感染可能起作用。因此，我们的研究可能会发现细菌感染和其他疾病之间有趣的联系。M蛋白的分子理解可以被认为是研究链球菌疾病的核心问题。我们的研究最终将有助于开发针对最重要和最危险的传染性病原体之一的迫切需要的新药或疫苗。

The emergence of bacteria resistant to almost all known antibiotics is one of the most important challenges for science. If no new prevention and treatment options for bacterial infectious are developed we may soon slip back into the state of the 19th century when people died of what we very recently thought of as trivial infections. In order to develop vaccines or treatments that differ significantly from drugs like penicillin we need to understand better the ways in which bacteria cause infections. To start with, bacteria have to gain a foothold in the human body. This is achieved through a variety of molecules present on the bacterial surface. These molecules, mostly proteins that often form hairlike structures, bind to human tissue at various sites in the body (e.g. throat, lung, guts, skin). An understanding of structure and function of these surface molecules is required for the development of vaccines. Also, if it was possible to prevent the bacteria from binding to the host, it would be possible to intervene with infections at an early stage. Streptococci are among the most common pathogens affecting humans and animals. Hundreds of millions of cases of strep throat are caused by the bacteria Streptococcus pyogenes every year. So far in countries with good health care penicillin treatment has been effective at keeping this common infection at bay. But as the sudden emergence of resistant pneumococci, C. difficile and MRSA has shown, we need to be prepared for the possibility of S. pyogenes developing penicillin resistance at any time (many strains are already resistant to various other drugs), which could have devastating consequences. For example, if not treated/treatable, strep throat can develop into life-threatening diseases such as rheumatic heart disease (RHD). Despite penicillin availability, RHD is one of the biggest killers of children and youths in India and other developing nations. In RHD our immune system turns against proteins in the body and destroys tissue of the heart valves. This devastating effect is only poorly understood but is known to be linked to a family of proteins (called M proteins) that cover the bacteria in what under the microscope looks like a furry coat.M proteins were discovered over 80 years ago, and were quickly realised to be required by streptococci for causing disease. Despite their abundance and obvious importance our understanding of how they function is very limited. This lack of progress can be explained with the unusual properties of M proteins, which make them difficult subjects for conventional molecular investigations. We have shown that significant progress can be made using a combination of complementary powerful biophysical techniques (NMR and EPR) that will reveal, at the level of atoms, what M proteins look like and how they work. In this project we will specifically investigate the binding of M proteins to the most abundant human protein, collagen. Collagen is found throughout the body, and its abundance makes it a particularly attractive target for bacteria, and may aid in establishing an infection. Importantly, bacterial binding to collagen may also be the underlying cause of RHD, since collagen is the main component of heart valve tissue. Intriguingly, there are similarities between rheumatic diseases caused by bacterial infections and common autoimmune diseases such as rheumatoid arthritis. The causes of rheumatoid arthritis are unknown but it has been suggested that bacterial infection may play a role. Therefore, our research may uncover interesting links between bacterial infections and other diseases.A molecular understanding of M proteins can be considered central to the problem of research into streptococcal diseases. Our investigations will ultimately contribute to the development of urgently required new drugs or vaccines for one of the most important and dangerous infectious agents.