Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs.
Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs.
复制标题
DOI：
10.1371/journal.ppat.1005016
复制
发表时间：
2015-06
期刊：
影响因子：
6.7
通讯作者：
Saphire EO
中科院分区：
文献类型：
--
作者：
Fusco ML;Hashiguchi T;Cassan R;Biggins JE;Murin CD;Warfield KL;Li S;Holtsberg FW;Shulenin S;Vu H;Olinger GG;Kim DH;Whaley KJ;Zeitlin L;Ward AB;Nykiforuk C;Aman MJ;Berry JD;Saphire EO
包括马尔堡病毒和埃博拉病毒在内的丝状病毒在这十年中已经在人类中引起了多次爆发。针对丝状病毒表面糖蛋白（GP）的抗体已被证明可在非人灵长类动物中提供挽救生命的治疗，但此类抗体通常是病毒特异性的。已经描述了许多针对埃博拉病毒的单克隆抗体（mAb）。相比之下，相对很少有针对马尔堡病毒的描述。在这里，我们提出了10个单克隆抗体引起的免疫小鼠使用重组粘蛋白缺失的GP从不同的马尔堡病毒（MARV）株。令人惊讶的是，针对MARV GP产生的两种mAb也与所有测试的埃博拉病毒（埃博拉病毒、苏丹病毒、本迪布焦病毒、莱斯顿病毒）的粘蛋白缺失GP核心发生交叉反应，但这些表位被粘蛋白样结构域本身不同地掩盖。发现该组中最有效的mAb识别GP 2亚基上的新“翼”特征，该特征是马尔堡特有的，并且在埃博拉中不存在。这些抗翼抗体中的两种在暴露后1小时在用MARV攻击的小鼠中分别赋予90%和100%的保护。这十年来，丝状病毒在人类中引起了多次爆发，包括安哥拉发生的90%致死性马尔堡病毒爆发和西非发生的重大持续埃博拉病毒爆发。病毒表面糖蛋白（GP）使丝状病毒能够感染宿主细胞，是免疫系统的主要靶标。靶向丝状病毒GP的抗体已被证明可在非人灵长类动物中提供挽救生命的治疗。然而，大多数已知的抗体仅对埃博拉病毒有反应性，而对其他新兴的丝状病毒没有反应性。在这项研究中，我们提出了10个抗体对马尔堡病毒，引起免疫小鼠使用其GP的工程形式。令人惊讶的是，两种抗体对埃博拉病毒（包括埃博拉、苏丹、本迪布焦、莱斯顿）表现出一定的交叉反应性。该组中的其他抗体识别GP的一部分上的新的“翼”特征，该特征是马尔堡特有的并且不存在于埃博拉病毒中，并且保护90%-100%的小鼠免于致死暴露。这些抗体，以及它们的结构和功能分析在这里，照亮方向前进的治疗马尔堡病毒。
The filoviruses, which include the marburg- and ebolaviruses, have caused multiple outbreaks among humans this decade. Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific. Many monoclonal antibodies (mAbs) have been described against Ebola virus. In contrast, relatively few have been described against Marburg virus. Here we present ten mAbs elicited by immunization of mice using recombinant mucin-deleted GPs from different Marburg virus (MARV) strains. Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves. The most efficacious mAbs in this panel were found to recognize a novel “wing” feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola. Two of these anti-wing antibodies confer 90 and 100% protection, respectively, one hour post-exposure in mice challenged with MARV. The filoviruses have caused multiple outbreaks among humans this decade, including a 90% lethal outbreak of Marburg virus in Angola and a significant, sustained outbreak of Ebola virus in West Africa. The viral surface glycoprotein (GP), which enables filoviruses to infect host cells, is the primary target of the immune system. Antibodies that target filovirus GP have been shown to provide life-saving therapy in nonhuman primates. However, the majority of known antibodies are only reactive against Ebola virus and not other emerging filoviruses. In this study, we present ten antibodies against Marburg virus, elicited by immunization of mice using engineered forms of its GP. Surprisingly, two antibodies exhibit some cross-reactivity to ebolaviruses (including species Ebola, Sudan, Bundibugyo, Reston). Other antibodies in this panel recognize a novel “wing” feature on a portion of GP that is unique to Marburg and does not exist in ebolaviruses, and protect 90%-100% of mice from lethal exposure. These antibodies, and their structural and functional analysis presented here, illuminate directions forward for therapeutics against Marburg virus.
登录
查看更多内容
影响因子：
64.8
作者：
Cote, Marceline;Misasi, John;Ren, Tao;Bruchez, Anna;Lee, Kyungae;Filone, Claire Marie;Hensley, Lisa;Li, Qi;Ory, Daniel;Chandran, Kartik;Cunningham, James
通讯作者：
Cunningham, James
影响因子：
5.4
作者：
Hood, Chantelle L.;Abraham, Jonathan;Nabel, Gary J.
通讯作者：
Nabel, Gary J.
影响因子：
56.9
作者：
KISSLING, RE;ROBINSON, RQ;WHITFIELD, SG
通讯作者：
WHITFIELD, SG
影响因子：
2.7
作者：
Kuhn, Jens H.;Becker, Stephan;Ebihara, Hideki;Geisbert, Thomas W.;Johnson, Karl M.;Kawaoka, Yoshihiro;Lipkin, W. Ian;Negredo, Ana I.;Netesov, Sergey V.;Nichol, Stuart T.;Palacios, Gustavo;Peters, Clarence J.;Tenorio, Antonio;Volchkov, Viktor E.;Jahrling, Peter B.
通讯作者：
Jahrling, Peter B.
影响因子：
3.7
作者：
Marzi A;Yoshida R;Miyamoto H;Ishijima M;Suzuki Y;Higuchi M;Matsuyama Y;Igarashi M;Nakayama E;Kuroda M;Saijo M;Feldmann F;Brining D;Feldmann H;Takada A
通讯作者：
Takada A