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The role of host cell membrane lipids in infection of microorganisms and in host defense mechanisms

宿主细胞膜脂质在微生物感染和宿主防御机制中的作用

基本信息

批准号：
13470494
负责人：
NISHIJIMA Masahiro
金额：
$ 5.7万
依托单位：
National Institute of Infectious Diseases
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

(1)Baculovirus gp64 envelope glycoprotein is a major component of the envelope of the budded virus and is involved in virus entry into the host cells by endocytosis. We investigated the cell-surface molecules important for infection of baculoyirus into mammalian cells by using a recombinant baculovirus, Ac64-CAluc, which has gp64 and luciferase genes under the polyhedrin and the CAG promoter, respectively. Inhibition with purified lipids and susceptibility to the mutant CHO hamster cell lines deficient in phospholipids synthesis suggested that the interaction of gp64 and phospholipids on the cell surface might play an important role in baculovirus infection into mammalian cells.(2) A convergent total synthesis of khafrefungin, a novel inhibitor of fungal sphingolipid syntheses isolated from the fermentation culture MF6020, has been developed, Khafrefungin derivatives have also been synthesized, and their antifungal activities have been measured to obtain information on the structure-ac … More tivity relationships. It is suggested that the configuration of the C4 position in khafrefungin appears to be crucial for inhibiting the activity of IPC synthase, the target enzyme of khafrefungin.(3) The expression of MD-2, which associates with Toll-like receptor (TLR)4 on the cell surface, confers LPS and LPS-mimetic Taxol responsiveness on TLR4. Alanine-scanning mutagenesis was performed to identify the mouse MD-2 residues important for conferring LPS and Taxol responsiveness on mouse TLR4, and for forming the cell surface TLR4-MD-2 complex recognized by anti-TLR4-MD-2 Ab MTS510. Our results suggest that the ability of MD-2 to form the cell surface mouse TLR4-mouse MD-2 complex recognized by MTS510 is essential for conferring LPS and Taxol responsiveness on TLR4, but not sufficient. In addition, the required residues at codon numbers 34, 85, 101, 122, and 153 for the ability of mouse MD-2 to confer LPS responsiveness are partly different from those for Taxol responsiveness.(4) Flavolipin, an amino acid-containing lipid isolated from Flavobacterium meningosepticum, induces many immune responses. In this study, we demonstrated the involvement of TLR4-MD-2 and CD14 in flavolipin signaling and the importance of the(R)-configuration of the flavolipin lipid moiety for the induction of an immune response via TLR4-MD-2. Less

（1）杆状病毒gp 64包膜糖蛋白是出芽病毒包膜的主要成分，参与病毒通过内吞作用进入宿主细胞。我们研究了杆状病毒感染哺乳动物细胞的重要细胞表面分子，通过使用重组杆状病毒，Ac 64-CAluc，其中gp 64和荧光素酶基因下的多角体蛋白和CAG启动子，分别。纯化的脂质和敏感性的突变CHO仓鼠细胞系缺乏磷脂合成的抑制表明，在杆状病毒感染到哺乳动物细胞的gp 64和细胞表面的磷脂的相互作用可能发挥重要作用。(2)本文报道了一种从发酵培养基MF 6020中分离得到的新型真菌鞘脂合成抑制剂卡氟芬净的收敛全合成方法，合成了卡氟芬净衍生物，并测定了它们的抗真菌活性，获得了卡氟芬净衍生物的结构和活性信息。 ...更多信息的关系。这表明，卡氟芬净的C4位置的配置似乎是至关重要的抑制IPC合酶的活性，卡氟芬净的靶酶。(3)MD-2的表达与细胞表面的Toll样受体（TLR）4相关，赋予LPS和LPS模拟紫杉醇对TLR 4的反应性。进行丙氨酸扫描诱变以鉴定对于赋予小鼠TLR 4对LPS和紫杉醇的反应性以及对于形成由抗TLR 4-MD-2 Ab MTS 510识别的细胞表面TLR 4-MD-2复合物重要的小鼠MD-2残基。我们的研究结果表明，MD-2形成由MTS 510识别的细胞表面小鼠TLR 4-小鼠MD-2复合物的能力对于赋予LPS和紫杉醇对TLR 4的反应性是必需的，但不是足够的。此外，小鼠MD-2赋予LPS反应性的能力所需的密码子编号34、85、101、122和153处的残基与紫杉醇反应性的残基部分不同。(4)黄伏脂是从脑膜败血黄杆菌中分离的含氨基酸的脂质，可诱导多种免疫应答。在这项研究中，我们证明了TLR 4-MD-2和CD 14参与黄伏脂信号传导，以及黄伏脂脂质部分的（R）-构型对于通过TLR 4-MD-2诱导免疫应答的重要性。少