基孔肯雅病毒(Chikungunya virus)已在非洲,、亞洲以及最近在歐洲導(dǎo)致傳染病流行,。它通過(guò)伊蚊(Aedes)傳播到人類?；卓涎挪《靖腥镜陌Y狀包括急性發(fā)熱,，同時(shí)還伴隨著能夠持續(xù)幾天、幾周或者甚至幾年的關(guān)節(jié)疼痛,。如今，來(lái)自新加坡的研究員Lucile Warter和他的同事們鑒定出該病毒的兩個(gè)區(qū)域,，而且這兩個(gè)區(qū)域能夠被人抗體所識(shí)別從而中和掉這種病毒,。研究人員有第一次證實(shí)這種病毒能夠直接地進(jìn)行細(xì)胞間傳播。這些發(fā)現(xiàn)可能有助于解釋這病病毒如何能夠躲避胞外中和抗體( neutralizing antibody)的結(jié)合而增加感染效率,。
為了發(fā)現(xiàn)抗體結(jié)合位點(diǎn),，研究人員將病毒與之前鑒定出的抗體一起孵育，然而分離出產(chǎn)生抗性的病毒變異株,。測(cè)序和結(jié)構(gòu)分析揭示抗性變異株在幾個(gè)區(qū)域發(fā)生突變,，這意味著這些區(qū)域是抗體結(jié)合位點(diǎn)。這些突變位于病毒的融合環(huán)“槽”和病毒包膜蛋白E2結(jié)構(gòu)域B中,。已證實(shí)結(jié)構(gòu)域B在中和抗體識(shí)別相關(guān)的RNA病毒中發(fā)揮著重要作用,。根據(jù)對(duì)抗性變異株的分析結(jié)果，研究人員猜測(cè)基孔肯雅病毒可能能夠直接地進(jìn)行細(xì)胞間傳播,。Warter和同事們通過(guò)在含有中和抗體的培養(yǎng)基中將遭受病毒感染的細(xì)胞與未感染的細(xì)胞一起培養(yǎng),，而證實(shí)了這一猜測(cè)。很多新的細(xì)胞被病毒感染,，但是在細(xì)胞外并沒(méi)有檢測(cè)到病毒顆粒,。
利用顯微鏡檢測(cè)遭受病毒感染的細(xì)胞也表明在細(xì)胞間接觸點(diǎn),，病毒顆粒濃度增加。直接進(jìn)行細(xì)胞間病毒傳播有利于直接傳播大量病毒顆粒到其他能夠開(kāi)始復(fù)制的細(xì)胞中,，同時(shí)又不會(huì)發(fā)生病毒進(jìn)入胞外空間的風(fēng)險(xiǎn),。不過(guò)，還需開(kāi)展進(jìn)一步研究以便鑒定出與這種傳播途徑相關(guān)的分子機(jī)制,，同時(shí)還需研究這種傳播是否能夠在體內(nèi)發(fā)生,。(生物谷：Bioon.com)
本文編譯自Investigation of Chikungunya virus yields two new antigens for vaccine development
doi:10.1371/journal.ppat.1002390
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Chikungunya Virus Neutralization Antigens and Direct Cell-to-Cell Transmission Are Revealed by Human Antibody-Escape Mutants
Chia Yin Lee1, Yiu-Wing Kam1, Jan Fric1, Benoit Malleret1, Esther G. L. Koh1, Celine Prakash1, Wen Huang1, Wendy W. L. Lee1, Cui Lin2, Raymond T. P. Lin2,3, Laurent Renia1, Cheng-I Wang1, Lisa F. P. Ng1,3, Lucile Warter
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.
