Mechanisms of immune evasion by Group A Streptococcus during skin infection

皮肤感染过程中 A 族链球菌的免疫逃避机制

• 批准号: 326692610
• 负责人: Dr. Angela Kurz
• 金额: --
• 依托单位: Centenary Institute
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/326692610?language=en
• 关键词: Mechanisms; immune; evasion; Group; Streptococcus

Infections by Group A Streptococcus (GAS), or Streptococcus pyogenes, represent a global health concern (Carapetis et al., 2005). They range from mild skin or throat infections to severe invasive diseases with potentially fatal outcome. Post-infectious complications such as acute rheumatic fever (ARF), rheumatic heart disease (RHD) and kidney diseases also cause serious health problems. The burden of GAS disease is disproportionately high in socio-economically disadvantaged groups, including the indigenous communities in Australia. The fact that there is no vaccine available (Pandey et al., 2012) emphasises the need to better understand GAS pathogenesis as well as immune responses during infection. In this proposal, I focus on NS88.2, a clinical isolate that was obtained from a patient with bacteraemia in the Northern Territory (McKay et al., 2004). Isolates from invasive infections often have mutations in their covS or covR genes, which encode the control of virulence regulatory sensor kinase (CovR/S) system (Maamary et al., 2010). The CovR/S system regulates up to 15% of GAS genes in response to environmental cues. NS88.2 contains a mutation in covS, which Dr. Sanderson-Smith has previously succeeded in repairing to produce an isogenic strain, termed NS88.2rep, with reduced virulence (Sanderson-Smith et al., 2008). This pair of bacterial strains is therefore a unique resource for studying GAS pathogenesis in vivo. In preliminary work, it was found that even a very low dose of NS88.2, injected intradermally, causes a fatal disease in mice, characterised by systemic bacterial dissemination. In contrast, NS88.2rep is cleared effectively by the innate immune system in the skin, and, hence, does not cause lethal disease. The flow cytometric and microscopic studies, both in vitro and in vivo, suggest that while NS88.2rep is efficiently phagocytosed, NS88.2 evades neutrophil uptake. These results suggest that the covS mutation enables NS88.2 to circumvent attack by neutrophils.Objective: In this application, I will dissect the immuno-evasive properties of NS88.2 using molecular, immunologic and intravital imaging approaches. I will thus obtain fundamental insight into how this important human pathogen evades host immunity to cause disease.Hypothesis: NS88.2 interferes with neutrophil uptake during skin infection in vivo, enabling rapid disseminationAim 1. Determine how NS88.2 evades the local neutrophil response in the skinAim 2. Determine how NS88.2 disseminates from the skin to the blood

A组链球菌（GAS）或化脓性链球菌的感染代表了全球健康问题（Carapetis等人，2005年）。它们的范围从轻微的皮肤或咽喉感染到严重的侵入性疾病，可能导致致命的后果。感染后并发症，如急性风湿热（ARF），风湿性心脏病（RHD）和肾脏疾病也会导致严重的健康问题。GAS疾病的负担在社会经济弱势群体中不成比例地高，包括澳大利亚的土著社区。没有可用的疫苗的事实（Pandey等人，2012）强调需要更好地理解GAS发病机制以及感染期间的免疫反应。在该提议中，我关注NS88.2，其是从北领地的菌血症患者获得的临床分离株（McKay等人，2004年）。来自侵入性感染的分离物通常在其covS或covR基因中具有突变，所述covS或covR基因编码毒力调节传感器激酶（CovR/S）系统的控制（Maamary等人，2010年）。CovR/S系统调节多达15%的GAS基因以响应环境线索。NS88.2含有covS中的突变，Sanderson-Smith博士先前已成功修复该突变以产生毒力降低的称为NS88.2rep的同基因菌株（Sanderson-Smith et al. 2008年）。因此，这对细菌菌株是研究体内GAS发病机制的独特资源。在初步工作中，发现即使是皮内注射非常低剂量的NS88.2，也会在小鼠中引起致命的疾病，其特征在于全身性细菌传播。相比之下，NS88.2rep被皮肤中的先天免疫系统有效清除，因此不会引起致命疾病。体外和体内的流式细胞术和显微镜研究表明，虽然NS88.2rep被有效吞噬，但NS88.2逃避中性粒细胞摄取。这些结果表明，covS突变使NS88.2规避攻击的中性粒细胞。目的：在此应用程序中，我将解剖的免疫逃避属性的NS88.2使用分子，免疫学和活体成像方法。因此，我将获得基本的洞察力如何这一重要的人类病原体逃避宿主免疫引起diseases.Hypothesis：NS88.2干扰中性粒细胞摄取皮肤感染过程中在体内，使快速disseminationAim 1。确定NS88.2如何逃避皮肤中的局部嗜中性粒细胞反应。确定NS88.2如何从皮肤传播到血液

项目成果

The lymphoid cell network in the skin

皮肤中的淋巴细胞网络

• DOI: 10.1111/imcb.12026
• 发表时间: 2018
• 期刊: Immunology and Cell Biology
• 影响因子: 4
• 作者: Tikoo S;Rohit J;Kurz AR;Weninger W
• 通讯作者: Weninger W