The immunomodulatory role of bacterial proteins

细菌蛋白的免疫调节作用

• 批准号: 7338811
• 负责人: Triantafyllos Chavakis
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338811
• 关键词: immunomodulatory; role; bacterial; proteins

Staphylococcus aureus can cause superficial skin infections and, systemic infections that entail spread through the blood stream. The organism expresses several factors that compromise the effectiveness of neutrophils and macrophages, the first line of defence against infection, as well as the subsequent adaptive response mediated by T-cells. S. aureus secretes proteins that inhibit complement activation and neutrophil and T-cell chemotaxis. Furthermore, S. aureus expresses several types of superantigen that corrupt the normal humoral immune response, resulting in anergy and immunosuppression.1) The interaction between S. aureus and host cells or the extracellular matrix is mediated by numerous cell-wall bound adhesins and / or by secreted proteins. The extracellular adherence protein (Eap) is such a secreted protein with a very broad binding repertoire for the extracellular matrix. Recently, we demonstrated a mechanism used by S. aureus to escape the host immune system that was attributed to the very potent anti-inflammatory function of Eap. In particular, we found Eap to undergo a direct interaction with ICAM-1 that resulted in the disruption of integrin LFA-1-dependent neutrophil-endothelial interactions and thereby inflammatory cell recruitment in vitro and in vivo (Nat Med, 2002, 8:687-693). A common clinical feature of S. aureus infected wounds is impaired healing. By using purified Eap as well as an Eap-positive and an Eap-deficient strain we found that Eap may account, at least in parts, for the delayed healing of S. aureus infected wounds. Besides its anti-inflammatory actions, the presence of Eap in wounds also inhibited neovascularization. 2)As the LFA-1/ICAM-1 interaction is also important for the transendothelial migration of T cells, we were prompted to investigate whether Eap could be feasible to interfere with T-cell adhesive mechanisms in autoimmune disease, and in particular, in experimental autoimmune encephalomyelitis (EAE). In vitro, Eap reduced adhesion of peripheral blood T cells to immobilized ICAM-1 as well as their transmigration of TNF-alpha activated human endothelium under static and shear flow conditions. These inhibitory effects were corroborated in two murine models of inflammation. In a delayed-type hypersensitivity model (DTH), both T-cell infiltration and the corresponding tissue edema were significantly reduced by Eap. In addition, administration of either purified or recombinant Eap prevented the development of EAE and markedly decreased infiltration of inflammatory cells into the CNS. Strikingly, intervention with Eap after the onset of EAE suppressed the disease. Thus, our findings indicate that Eap could represent an attractive treatment for autoimmune neuro-inflammatory disorders, such as multiple sclerosis. This hypothesis is worth evaluating in further preclinical and clinical studies. 3) The resemblance of Eap with the C-terminus of a staphylococcal superantigen (the part of superantigens that binds to the TCR) will be further investigated as a potential mechanism for the immunosuppressive role of Eap.4) Eap binds to osteopontin and can tehreby interfere with the interaction of osteopontin with alphavbeta3 integrin. As the latter interaction is crucial for bone metastasis of breast cancer cells, the potential of Eap to block breast cancer metastasis will be evaluated.

金黄色葡萄球菌会引起浅表皮肤感染，并导致需要通过血流传播的全身感染。该生物表达了几个因素，这些因素损害了中性粒细胞和巨噬细胞的有效性，对感染的第一道防线以及随后由T细胞介导的自适应反应。金黄色葡萄球菌分泌抑制补体激活以及中性粒细胞和T细胞趋化性的蛋白质。此外，金黄色葡萄球菌表达了几种损坏正常体液免疫反应的超抗原，从而导致厌食和免疫抑制。1）金黄色葡萄球菌与宿主细胞与宿主细胞之间的相互作用或细胞外基质是由许多细胞壁结合的粘合剂和 /或由秘密蛋白质介导的。细胞外粘着蛋白（EAP）是一种分泌的蛋白质，对于细胞外基质，具有非常宽的结合曲目。最近，我们证明了金黄色葡萄球菌用来逃避宿主免疫系统的一种机制，该机制归因于EAP的非常有效的抗炎功能。特别是，我们发现EAP与ICAM-1进行直接相互作用，从而导致整联蛋白LFA-1依赖性中性粒细胞 - 内皮相互作用中断，从而在体外和体外炎性细胞募集（Nat Med，2002，8：687-693）。金黄色葡萄球菌感染伤口的常见临床特征是愈合受损。通过使用纯化的EAP以及EAP阳性和EAP缺陷菌株，我们发现EAP至少在某些部分中可以考虑到金黄色葡萄球菌感染的伤口的延迟愈合。除了其抗炎作用外，伤口中EAP的存在还抑制了新血管形成。 2）由于LFA-1/ICAM-1相互作用对于T细胞的跨内皮迁移也很重要，因此我们提示我们研究EAP是否可以可行地干扰自身免疫性疾病中的T细胞粘合剂机制，尤其是在实验性自身免疫性的肾上腺瘤炎（EAE）中。在体外，EAP降低了外周血T细胞对固定的ICAM-1的粘附以及它们在静态和剪切流条件下激活的TNF-Alpha激活人内皮的迁移。这些抑制作用在两个炎症的鼠模型中得到了证实。在延迟类型的超敏反应模型（DTH）中，T细胞浸润和相应的组织水肿均通过EAP显着降低。此外，施用纯化或重组EAP可以阻止EAE的发展，并显着降低了炎症细胞进入中枢神经系统的发展。令人惊讶的是，EAE发作后与EAP的干预抑制了该疾病。因此，我们的发现表明，EAP可以代表自身免疫性神经炎症性疾病（例如多发性硬化症）的有吸引力的治疗方法。在进一步的临床前和临床研究中，该假设值得评估。 3）EAP与葡萄球菌超抗原的C末端（与TCR结合的超抗原的一部分）的C末端将作为EAP.4）EAP的免疫抑制作用的潜在机制进行研究。由于后一种相互作用对于乳腺癌细胞的骨转移至关重要，因此将评估EAP阻断乳腺癌转移的潜力。