眾所周知,，不成熟的登革熱病毒(DENV)是沒有感染性的，但是最近荷蘭格羅寧根大學的研究人員Jolanda M. Smit等人卻發(fā)現(xiàn)：抗前體膜(prM)的抗體會導致這種不成熟病毒對有Fcγ受體表達的細胞具有傳染性,。在DENV抗體與病毒包膜以及前體膜(prM)蛋白相互作用后,，會引起抗體依賴性病毒感染增強,，結果導致更嚴重的疾病,。相關論文發(fā)表在3月14日的美國科學公共圖書館—綜合》（PLoS One）上,。
由于病毒在成熟過程中低效率的加工，不成熟的DENV顆粒會極其豐富的存在于標準病毒的制劑中,?？墒墙Y構分析顯示包膜蛋白暴露于不成熟的病毒顆粒中。這提示了研究人員去調查是否是包膜蛋白的抗體促使了這些不成熟的病毒顆粒具有感染性,。
基于明顯的結構區(qū)域差異,，研究人員分析了具有增強感染作用的27個抗包膜蛋白的抗體，結果發(fā)現(xiàn),，里面有23個不成熟顆粒,，其中有15個增強了不成熟的DENV的感染活性。在發(fā)現(xiàn)這個結果的重要性后,，他們在建立好的感染西尼羅河病毒(WNV)的老鼠模型身上做了活體的實驗,。結果顯著表明，在抗包膜蛋白單克隆抗體或者是免疫血清的調理下,，被不成熟的WNV感染后的老鼠,，會產生了劑量依賴方式的致死感染。然而,，沒有抗體作用的不成熟的WNV不會引起發(fā)病或者死亡。
此外,，對標準DENV制劑的感染增強實驗研究表明,，標準病毒制劑中出現(xiàn)的由前體膜包含的病毒顆粒,，會促進抗體依賴性增強感染?？偟膩碚f,，這些結果說明一個問題：抗結構蛋白prM以及包膜蛋白的抗體，通過增強前體膜包含不成熟的或者是部分成熟的病毒顆粒的感染,，可以促進發(fā)病,。（生物谷Bioon.com）
doi: 10.1371/journal.pone.0029957
PMC:
PMID:
Antibodies against the Envelope Glycoprotein Promote Infectivity of Immature Dengue Virus Serotype 2
Júlia M. da Silva Voorham, Izabela A. Rodenhuis-Zybert, Nilda Vanesa Ayala Nu?ez, Tonya M. Colpitts, Heidi van der Ende-Metselaar, Erol Fikrig, Michael S. Diamond, Jan Wilschut1, Jolanda M. Smit.
Cross-reactive dengue virus (DENV) antibodies directed against the envelope (E) and precursor membrane (prM) proteins are believed to contribute to the development of severe dengue disease by facilitating antibody-dependent enhancement of infection.We and others recently demonstrated that anti-prM antibodies render essentially non-infectious immature DENV infectious in Fcγ-receptor-expressing cells. Immature DENV particles are abundantly present in standard (st) virus preparations due to inefficient processing of prM to M during virus maturation. Structural analysis has revealed that the E protein is exposed in immature particles and this prompted us to investigate whether antibodies to E render immature particles infectious. To this end, we analyzed the enhancing properties of 27 anti-E antibodies directed against distinct structural domains.Of these, 23 bound to immature particles, and 15 enhanced infectivity of immature DENV in a furin-dependent manner. The significance of these findings was subsequently tested in vivo using the well-established West Nile virus (WNV) mouse model. Remarkably, mice injected with immature WNV opsonized with anti-E mAbs or immune serum produced a lethal infection in a dose-dependent manner, whereas in the absence of antibody immature WNV virions caused no morbidity or mortality.Furthermore, enhancement infection studies with standard (st) DENV preparations opsonized with anti-E mAbs in the presence or absence of furin inhibitor revealed that prM-containing particles present within st virus preparations contribute to antibody-dependent enhancement of infection. Taken together, our results support the notion that antibodies against the structural proteins prM and E both can promote pathogenesis by enhancing infectivity of prM-containing immature and partially mature flavivirus particles.
