IMPC Testing dst1 in susceptibility to infection

IMPC 测试 dst1 对感染的易感性

• 批准号: MR/R01454X/1
• 负责人: Shiranee Sriskandan
• 金额: $ 4.67万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR01454X%2F1
• 关键词: IMPC; Testing; dst1; susceptibility; infection

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.

由A组链球菌引起的坏死性筋膜炎（NF）是一种致命的感染，它破坏皮肤下的结缔组织;虽然罕见，但它会杀死30%的受影响者。在过去的20年里，英国的病例数量有所增加，尽管进行了手术，抗生素和支持性治疗，仍可能发生死亡。尽管进行了挽救生命的手术，许多人仍留下永久性疤痕或残疾。病例通常发生在相对轻微的皮肤破裂（包括水痘）或注射后，可能是由于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之前没有受伤或皮肤破裂。在英国每年大约有400例A组链球菌NF;与其他类型的NF不同，受影响的患者通常没有其他内科或外科疾病。因此，感染在发生时是毁灭性的。似乎有可能是一种遗传因素，使一些人比其他人更容易发展A组链球菌NF。我们与英国NF患者支持小组一起进行了一项小型研究，以确定可能在A组链球菌NF患者中过度表达的遗传因素。我们发现，在一个特定的基因称为DST的遗传差异存在于两个儿童谁有非常严重的NF;这一发现也被视为在一些成人NF。DST基因产生一种蛋白质，这种蛋白质是所谓的半桥粒的主要部分-这些是将皮肤层保持在一起的粘性斑块。一些NF患者在其他蛋白质中也存在基因缺陷，这些蛋白质在半桥粒中也是必需的，这表明半桥粒的异常可能是NF的一般风险因素。半桥粒允许表皮中最底层的皮肤细胞粘附到称为基底膜的层上，基底膜下方是称为真皮和皮下结缔组织或筋膜的更深的组织。如果DST的一个基因拷贝有问题（如我们研究的患者）或缺失，可能是皮肤层结合不太牢固，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。为了通过实验测试这一点，我们将使用缺乏一个已经产生的DST基因拷贝的小鼠;这些小鼠在其他方面都很健康。我们将确定这些小鼠是否更容易发展A组链球菌NF的早期变化，与具有完整基因拷贝的小鼠相比。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。每次实验持续时间短，因此小鼠不会生病。在NF开始之前的感染早期阶段进行细菌测量将是可能的。这些结果将揭示只有一个健康的DST基因拷贝是否会导致侵袭性A组链球菌感染和NF的风险增加。这将是重要的，因为目前，仅仅一个异常DST基因的存在还没有被认为是有害的。如果与A组链球菌NF有联系，则可以提醒这些患者注意风险增加，例如，可能会建议接受及时的抗生素治疗喉咙痛或可能由A组链球菌引起的其他感染。