在淋病奈瑟菌(Neisseria gonorrhoeae,NG)6种保守外膜蛋白中筛选优势表位,设计淋病奈瑟菌多表位亚单位疫苗并模拟其免疫效果。首先,通过C-ImmSim在线服务器对6种外膜蛋白进行计算机免疫模拟,并分别从细胞毒性T细胞(cytotoxic T lymphocy...在淋病奈瑟菌(Neisseria gonorrhoeae,NG)6种保守外膜蛋白中筛选优势表位,设计淋病奈瑟菌多表位亚单位疫苗并模拟其免疫效果。首先,通过C-ImmSim在线服务器对6种外膜蛋白进行计算机免疫模拟,并分别从细胞毒性T细胞(cytotoxic T lymphocyte,CTL)、辅助性T细胞(helper T cell,Th cell)及B细胞免疫反应强的外膜蛋白中筛选用于构建多表位亚单位疫苗的优势CTL表位、Th细胞表位和B细胞表位。其次,在对各优势表位进行抗原性、致敏性和毒性分析后,将不同排列组合的优势表位与抗菌肽及PADRE序列连接起来,设计出多表位亚单位疫苗。再次,对所设计的各种多表位亚单位疫苗进行计算机免疫模拟,以评价其体液免疫和细胞免疫的效果。最后,对筛选出的免疫效果较好的候选亚单位疫苗进行抗原性、致敏性、理化性质、溶解性评估以及二级结构分析,以确保候选亚单位疫苗符合疫苗设计标准。结果显示,筛选出符合要求的优势候选CTL表位8个、Th细胞表位10个和B细胞表位14个;共设计出64种多表位亚单位疫苗,其中3种亚单位疫苗的免疫模拟结果最佳,均满足抗原性强、对人体无致敏性及无细胞毒性的要求,且均为亲水性、耐热性较好的稳定蛋白质,同时能在大肠杆菌中实现可溶性的过表达,与抗体的亲和性也较强,符合疫苗设计的标准。研究结果表明,以C-ImmSim为主的生物信息学预测方法在多表位亚单位疫苗的反向设计及其免疫效果的高通量初步筛选方面具有良好的应用前景。本研究为淋病奈瑟菌疫苗研发提供了一种新的有效途径。展开更多
The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway,comprised of cyclic GMP-AMP synthase(cGAS),stimulator of interferon genes(STING)...The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway,comprised of cyclic GMP-AMP synthase(cGAS),stimulator of interferon genes(STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases.After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2’3’-c GAMP for the activation of endoplasmic reticulum(ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosoliclocalized cGAS. Detailed delineation of this pathway,including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.展开更多
EB病毒(epstein-barr virus,EBV)在人群中的感染率高达90%,其能够通过对宿主的免疫调控作用在人体内建立长期感染。众多肿瘤的发生及发展与EBV对宿主免疫的调控密切相关,但目前关于EBV的免疫调控作用机制尚未完全阐明。EBV在不同的感染...EB病毒(epstein-barr virus,EBV)在人群中的感染率高达90%,其能够通过对宿主的免疫调控作用在人体内建立长期感染。众多肿瘤的发生及发展与EBV对宿主免疫的调控密切相关,但目前关于EBV的免疫调控作用机制尚未完全阐明。EBV在不同的感染状态下均发展出了一系列对宿主的免疫调控策略,即主要通过靶向Toll样受体(Toll like receptors,TLRs)信号通路,利用或限制部分免疫效应以促进长期感染的建立和逃避宿主免疫监控,从而维持EBV基因组的稳定存在。概述了EBV在潜伏期和裂解期与宿主之间的相互作用,探讨了EBV逃避宿主免疫的策略,旨在为病毒感染防治和病毒相关肿瘤的治疗提供基础理论依据及研究思路。展开更多
文摘在淋病奈瑟菌(Neisseria gonorrhoeae,NG)6种保守外膜蛋白中筛选优势表位,设计淋病奈瑟菌多表位亚单位疫苗并模拟其免疫效果。首先,通过C-ImmSim在线服务器对6种外膜蛋白进行计算机免疫模拟,并分别从细胞毒性T细胞(cytotoxic T lymphocyte,CTL)、辅助性T细胞(helper T cell,Th cell)及B细胞免疫反应强的外膜蛋白中筛选用于构建多表位亚单位疫苗的优势CTL表位、Th细胞表位和B细胞表位。其次,在对各优势表位进行抗原性、致敏性和毒性分析后,将不同排列组合的优势表位与抗菌肽及PADRE序列连接起来,设计出多表位亚单位疫苗。再次,对所设计的各种多表位亚单位疫苗进行计算机免疫模拟,以评价其体液免疫和细胞免疫的效果。最后,对筛选出的免疫效果较好的候选亚单位疫苗进行抗原性、致敏性、理化性质、溶解性评估以及二级结构分析,以确保候选亚单位疫苗符合疫苗设计标准。结果显示,筛选出符合要求的优势候选CTL表位8个、Th细胞表位10个和B细胞表位14个;共设计出64种多表位亚单位疫苗,其中3种亚单位疫苗的免疫模拟结果最佳,均满足抗原性强、对人体无致敏性及无细胞毒性的要求,且均为亲水性、耐热性较好的稳定蛋白质,同时能在大肠杆菌中实现可溶性的过表达,与抗体的亲和性也较强,符合疫苗设计的标准。研究结果表明,以C-ImmSim为主的生物信息学预测方法在多表位亚单位疫苗的反向设计及其免疫效果的高通量初步筛选方面具有良好的应用前景。本研究为淋病奈瑟菌疫苗研发提供了一种新的有效途径。
基金supported by the Natural Science Foundation of Zhejiang Province(LY23C190002)National Natural Science Foundation of China(32173004)Natural Science Foundation of Ningbo City(202003N4011)。
文摘The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway,comprised of cyclic GMP-AMP synthase(cGAS),stimulator of interferon genes(STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases.After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2’3’-c GAMP for the activation of endoplasmic reticulum(ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosoliclocalized cGAS. Detailed delineation of this pathway,including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.
文摘EB病毒(epstein-barr virus,EBV)在人群中的感染率高达90%,其能够通过对宿主的免疫调控作用在人体内建立长期感染。众多肿瘤的发生及发展与EBV对宿主免疫的调控密切相关,但目前关于EBV的免疫调控作用机制尚未完全阐明。EBV在不同的感染状态下均发展出了一系列对宿主的免疫调控策略,即主要通过靶向Toll样受体(Toll like receptors,TLRs)信号通路,利用或限制部分免疫效应以促进长期感染的建立和逃避宿主免疫监控,从而维持EBV基因组的稳定存在。概述了EBV在潜伏期和裂解期与宿主之间的相互作用,探讨了EBV逃避宿主免疫的策略,旨在为病毒感染防治和病毒相关肿瘤的治疗提供基础理论依据及研究思路。
