IMPC Testing dst1 in susceptibility to infection

由A组链球菌引起的坏死性筋膜炎是一种致命的感染，它破坏皮肤下的结缔组织；虽然罕见，但30%的患者会死亡。在过去的20年里，英国的病例数量有所上升，尽管进行了手术、抗生素和支持性治疗，但仍有可能发生死亡。尽管做了挽救生命的手术，许多人还是留下了永久的伤疤或残疾。病例通常发生在相对较小的皮肤破裂之后，包括水痘或注射，可能是因为允许A组链球菌进入并穿过皮肤外层。然而，大约四分之一的患者以前根本没有受伤或皮肤破裂。在英国，每年大约有400例A组链球菌性神经炎；与其他类型的神经炎不同，受影响的患者通常没有其他内科或外科疾病。因此，当感染发生时，它是毁灭性的。似乎可能存在一种遗传因素，使一些人比其他人更有可能患上A群链球菌神经衰弱。我们与英国的核因子患者支持小组一起进行了一项小型研究，以确定在患有A组链球菌核因子的患者中可能存在过度表达的遗传因素。我们发现，在两名患有非常严重的神经营养不良的儿童中，存在一种名为DST的特定基因的遗传差异；这一发现在一些患有神经营养不良的成年人中也可以看到。DST基因产生一种蛋白质，它是所谓的半桥体的主要组成部分--这些半桥体是将皮肤各层粘连在一起的粘性斑块。部分NF患者在半桥粒中所必需的其他蛋白质中存在基因缺陷，提示半桥粒异常可能是NF的一般危险因素。半桥粒允许表皮中最底层的皮肤细胞附着在被称为基底膜的一层上，基底膜下面是被称为真皮和皮下结缔组织或筋膜的更深层次的组织。如果DST的一个基因拷贝有故障(就像我们研究的患者的情况)或丢失，可能是皮肤层结合得不那么紧密，A组链球菌等细菌可能更容易渗透到更深的组织中，引发这些层和NF的感染。为了进行实验测试，我们将使用缺乏已经产生的DST基因拷贝的小鼠；这些小鼠在其他方面是健康的。我们将确定，与拥有完整基因拷贝的小鼠相比，这些小鼠是否更容易发生A组链球菌核因子的早期变化。实验将涉及皮肤暴露于A组链球菌。然后测量皮肤下的A组链球菌。每次实验的持续时间都很短，因此小鼠不会生病。在核因子开始之前，在感染的早期阶段对细菌进行测量将是可能的。总而言之，这些结果将揭示只有一个健康的DST基因副本是否会导致侵袭性A群链球菌感染和核因子风险增加。这一点很重要，因为目前，只有一个异常的DST基因的存在还没有被认为是有害的。如果与A群链球菌核因子有关，这类患者可能会被告知风险增加，并可能被建议立即接受抗生素治疗，以治疗喉咙痛或其他可能由A群链球菌引起的感染。

Necrotising fasciitis (NF) due to group A streptococcus is a lethal infection that destroys the connective tissues beneath the skin; although rare, it kills 30% of those affected. The number of cases in the UK has risen over the last 20 years and deaths can occur despite surgery, antibiotics and supportive treatment. Many people are left permanently scarred or disabled despite life-saving surgery. Cases frequently arise following comparatively trivial skin breaks including chickenpox, or injections, presumably by allowing group A streptococci to enter and pass through the outer skin layer. However, around a quarter of patients have no prior injury or skin break at all. There are roughly 400 cases of group A strep NF per year in England; unlike other types of NF, patients affected often have no other medical or surgical illnesses. As such, the infection is devastating when it occurs. It seems likely that there could be a genetic factor that makes some people more likely to develop group A strep NF than others. Together with the UK's NF patient support group, we undertook a small study to identify genetic factors that might be over-represented in patients who have had group A strep NF. We found that genetic differences in one particular gene called DST were present in two children who had very severe NF; this finding was also seen in some of the adults with NF. The DST gene produces a protein that is a major part of so-called hemidesmosomes - these are sticky patches that hold the layers of skin together. Some of the patients with NF had gene defects in other proteins that are also essential in hemidesmosomes, suggesting that abnormalities of the hemidesmosome might be a general risk factor for NF. Hemidesmosomes allow the bottom-most layer of skin cells in the epidermis to stick to a layer known as the basement membrane, below which lies the deeper tissues known as the dermis and subcutaneous connective tissue or fascia. If one gene copy of DST is faulty (as in the case of the patients we studied) or missing, it is possible that the skin layers are less strongly bound together, and bacteria such as group A strep might find it easier to penetrate into the deeper tissues to trigger infection of these layers and NF.In order to test this experimentally, we will use mice that lack one copy of the DST gene that have already been generated; these mice are otherwise healthy. We will determine whether these mice are more prone to develop early changes of group A strep NF, compared with mice that have intact copies of the gene. Experiments will involve skin exposure to group A strep. followed by measurements of group A strep under the skin. Each experiment will be of short duration hence mice will not become sick. It will be possible to make measurements of bacteria at an early stage of infection before NF begins. Together the results will reveal whether having only one healthy copy of the DST gene results in increased risk of invasive group A strep infection and NF. This will be important because, at present, the presence of just one abnormal DST gene is not recognised to be harmful. If there is a link to group A strep NF, such patients could be alerted to the increased risk, and might, for example, be advised to receive prompt antibiotic treatment for sore throats or other infections likely to be caused by group A streptococci.