Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants.
Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants.
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DOI：
10.1371/journal.ppat.1002390
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Warter L
中科院分区：
文献类型：
--
作者：
Lee CY;Kam YW;Fric J;Malleret B;Koh EG;Prakash C;Huang W;Lee WW;Lin C;Lin RT;Renia L;Wang CI;Ng LF;Warter L
基孔肯雅病毒（CHIKV）是一种甲病毒，在整个非洲和亚洲引起许多流行病，引起感染性关节炎，据报道与新生儿和老年人的致命感染有关。先前在动物模型中的研究表明，体液免疫可以保护免受CHIKV感染，但尽管B细胞驱动的干预策略具有潜在功效，但目前还没有病毒特异性疫苗或疗法。此外，据报道，CHIKV可在人体中引发持久的病毒特异性IgM，并在非人灵长类动物中建立长期持续性，这表明该病毒可能会逃避免疫防御，从而在人体中建立慢性感染。然而，CHIKV可能采用的免疫逃避机制仍不清楚。我们先前描述了两种有效中和CHIKV感染的人单克隆抗体。在本报告中，我们已经表征了逃避抗体依赖性中和的CHIKV突变体，以鉴定CHIKV E2结构域B和融合环“沟”作为CHIKV与这些抗体相互作用的主要决定因素。此外，我们还首次证明了直接CHIKV细胞间传播，作为涉及E2结构域A的机制，并且与病毒对抗体依赖性中和的抗性相关。与人类保护性免疫相关的CHIKV亚结构域的鉴定将为CHIKV特异性亚结构域疫苗接种策略的开发铺平道路。此外，CHIKV细胞间传播及其在建立CHIKV持久性中的可能作用的明确证明也将为未来抗病毒干预的发展提供信息。这些数据为CHIKV-宿主相互作用提供了新的线索，这将有助于对抗人类CHIKV感染，并为CHIKV发病机制的未来研究提供信息。基孔肯雅病毒（CHIKV）通过蚊子叮咬传播，并引起一种发热性疾病，其特征通常是持续的关节疼痛。直到最近，CHIKV疫情仅限于非洲和亚洲的热带地区。然而，自2007年以来，继印度洋和东南亚的大规模CHIKV流行之后，欧洲温带地区也报告了CHIKV。随着蚊子栖息地的扩大，病毒传播可能会变得更加普遍，但目前还没有疫苗或CHIKV特异性治疗方法。我们先前描述了两种有效阻断细胞CHIKV感染的人抗体。在本报告中，我们已经表征了逃避中和的CHIKV突变体，以鉴定参与CHIKV与这些抗体相互作用的病毒包膜的亚结构域，从而为开发CHIKV特异性亚结构域疫苗接种策略打开了大门。我们还首次证明了CHIKV可以直接在细胞之间传播，绕过细胞外空间的运输。这种传播模式与病毒对抗体中和的抗性相关，可能在建立持续性CHIKV感染中起关键作用。总之，这些发现将有助于设计对抗CHIKV感染的新策略，并将为未来CHIKV发病机制的研究提供信息。
Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics throughout Africa and Asia, causing infectious arthritis and reportedly linked with fatal infections in newborns and elderly. Previous studies in animal models indicate that humoral immunity can protect against CHIKV infection, but despite the potential efficacy of B-cell-driven intervention strategies, there are no virus-specific vaccines or therapies currently available. In addition, CHIKV has been reported to elicit long-lasting virus-specific IgM in humans, and to establish long-term persistence in non-human primates, suggesting that the virus might evade immune defenses to establish chronic infections in man. However, the mechanisms of immune evasion potentially employed by CHIKV remain uncharacterized. We previously described two human monoclonal antibodies that potently neutralize CHIKV infection. In the current report, we have characterized CHIKV mutants that escape antibody-dependent neutralization to identify the CHIKV E2 domain B and fusion loop “groove” as the primary determinants of CHIKV interaction with these antibodies. Furthermore, for the first time, we have also demonstrated direct CHIKV cell-to-cell transmission, as a mechanism that involves the E2 domain A and that is associated with viral resistance to antibody-dependent neutralization. Identification of CHIKV sub-domains that are associated with human protective immunity, will pave the way for the development of CHIKV-specific sub-domain vaccination strategies. Moreover, the clear demonstration of CHIKV cell-to-cell transmission and its possible role in the establishment of CHIKV persistence, will also inform the development of future anti-viral interventions. These data shed new light on CHIKV-host interactions that will help to combat human CHIKV infection and inform future studies of CHIKV pathogenesis. Chikungunya virus (CHIKV) is transmitted by mosquito bites and causes a febrile disease that is often characterized by persistent joint pain. Until recently, CHIKV outbreaks were limited to tropical areas of Africa and Asia. However, since 2007, following a large CHIKV epidemic in the Indian Ocean and South-East Asia, CHIKV has also been reported in temperate European regions. As mosquito habitats expand, virus dissemination may become more prevalent, but there are currently no vaccines or CHIKV-specific treatments available. We previously described two human antibodies that potently block cellular CHIKV infection. In the current report, we have characterized CHIKV mutants that escape neutralization to identify sub-domains of the virus envelope which are involved in CHIKV interaction with these antibodies, thereby opening the door for the development of CHIKV-specific sub-domain vaccination strategies. For the first time, we have also demonstrated that CHIKV can be directly transmitted between cells, bypassing transport through the extra-cellular space. This mode of dissemination, which is associated with viral resistance to antibody neutralization, may play a critical role in the establishment of persistent CHIKV infection. Together, these findings will aid the design of new strategies to combat CHIKV infection and will inform future studies of CHIKV pathogenesis.
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影响因子：
3.8
作者：
Hunt, Ann R.;Frederickson, Shana;Blair, Carol D.
通讯作者：
Blair, Carol D.
影响因子：
5.4
作者：
FLYNN, DC;MEYER, WJ;JOHNSTON, RE
通讯作者：
JOHNSTON, RE
DOI：
10.1073/pnas.96.24.13910
发表时间：
1999-11-23
影响因子：
11.1
作者：
Drake, JW;Holland, JJ
通讯作者：
Holland, JJ
影响因子：
7.8
作者：
KIELIAN, M;HELENIUS, A
通讯作者：
HELENIUS, A
影响因子：
3.8
作者：
Jerzak, G;Bernard, KA;Ebel, GD
通讯作者：
Ebel, GD