Dengue virus specific IgY provides protection following lethal dengue virus challenge and is neutralizing in the absence of inducing antibody dependent enhancement.
Dengue virus specific IgY provides protection following lethal dengue virus challenge and is neutralizing in the absence of inducing antibody dependent enhancement.
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DOI：
10.1371/journal.pntd.0005721
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发表时间：
2017-07
影响因子：
3.8
通讯作者：
Bradley DS
中科院分区：
文献类型：
--
作者：
Fink AL;Williams KL;Harris E;Alvine TD;Henderson T;Schiltz J;Nilles ML;Bradley DS
登革出血热(DHF)和登革休克综合征(DSS)是一种严重的疾病表现，可在连续感染不同的登革病毒血清型(DENV1-4)后发生。目前，还没有获得许可的治疗DENV引起的疾病的疗法。DHF和DSS被认为是由血清型交叉反应抗体介导的，这些抗体通过与病毒抗原结合促进抗体依赖增强，然后在靶髓系细胞上结合Fcγ受体(FcγR)。利用基因工程的DENV特异性抗体，已经证明血清型交叉反应抗体的Fc部分与FcγR之间的相互作用是诱发ADE所必需的。此外，研究还表明，这些抗体与其未修饰的变异体一样具有中和性，不能诱发ADE，并且在抗体增强的致死性感染后具有治疗作用。因此，我们推测，不与哺乳动物FcγR相互作用的禽类IgY将为DENV诱导的疾病提供一种新的治疗方法。在此，我们证明了鹅源抗DENV2抗体在体外中和了DENV2，并且不能诱发ADE。在致死性DENV2感染后24小时给药，抗DENV2抗体在体内也有保护作用。我们还能够通过表位映射证明全长和选择性剪接的抗DENV2 IgY识别不同的表位，包括以前未识别的表位。这些观察结果为鹅源抗DENV2抗体的潜在治疗应用提供了证据。登革出血热(DHF)和登革休克综合征(DSS)是继发性异型登革病毒(DENV)感染后的严重疾病表现。DENV每年感染近4亿人，目前还没有获得许可的疗法来治疗DENV引起的疾病。DHF和DSS是由血清型交叉反应抗体介导的，这些抗体通过与病毒抗原结合促进抗体依赖增强，然后与周围细胞上的Fcγ受体(FcγR)结合。ADE导致免疫反应增强，并在一定程度上介导了继发性DENV感染的发病机制。研究人员开发了一种ADE诱导的严重DENV动物模型，在该模型中，通过基因工程消除FCR结合的抗DENV2抗体具有治疗和预防效果。我们的研究表明，未经基因修饰的禽源性抗DENV2卵黄抗体在体外和体内都能对致死性DENV攻击提供保护。IgY已成为一种有吸引力的替代治疗性抗体，因为它的生物学特性使其能够防止哺乳动物抗体用于人类免疫治疗时的一些不良反应。具体来说，卵黄抗体不与哺乳动物补体或类风湿因子结合，已被证明对人类食用非常安全。无需修饰，抗DENV2卵黄抗体可以快速生产，并可能成为治疗全球登革热的良好选择。
Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are severe disease manifestations that can occur following sequential infection with different dengue virus serotypes (DENV1-4). At present, there are no licensed therapies to treat DENV-induced disease. DHF and DSS are thought to be mediated by serotype cross-reactive antibodies that facilitate antibody-dependent enhancement (ADE) by binding to viral antigens and then Fcγ receptors (FcγR) on target myeloid cells. Using genetically engineered DENV-specific antibodies, it has been shown that the interaction between the Fc portion of serotype cross-reactive antibodies and FcγR is required to induce ADE. Additionally, it was demonstrated that these antibodies were as neutralizing as their non-modified variants, were incapable of inducing ADE, and were therapeutic following a lethal, antibody-enhanced infection. Therefore, we hypothesized that avian IgY, which do not interact with mammalian FcγR, would provide a novel therapy for DENV-induced disease. We demonstrate here that goose-derived anti-DENV2 IgY neutralized DENV2 and did not induce ADE in vitro. Anti-DENV2 IgY was also protective in vivo when administered 24 hours following a lethal DENV2 infection. We were also able to demonstrate via epitope mapping that both full-length and alternatively spliced anti-DENV2 IgY recognized different epitopes, including epitopes that have not been previously identified. These observations provide evidence for the potential therapeutic applications of goose-derived anti-DENV2 IgY. Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are severe disease manifestations following secondary heterotypic dengue virus (DENV) infections. DENV infects almost 400 million people annually and there are currently no licensed therapies to treat DENV-induced disease. DHF and DSS are mediated by serotype cross-reactive antibodies that facilitate antibody dependent enhancement (ADE) by binding to viral antigens and then Fcγ receptors (FcγR) on surrounding cells. ADE results in a heightened immune response and in part mediates the pathogenesis of secondary DENV infections. Researchers have developed an animal model of ADE-induced severe DENV in which anti-DENV2 antibodies genetically engineered to eliminate FcR binding have therapeutic and prophylactic efficacy. Our study suggests that avian-derived anti-DENV2 IgY, without genetic modification, is able to provide protection both in vitro and against a lethal DENV challenge in vivo. IgY has emerged as an attractive, alternative therapeutic antibody because of its biological characteristics that enable it to prevent some of the adverse reactions that mammalian antibodies have when used for human immunotherapy. Specifically, IgY does not bind to mammalian complement or rheumatoid factor and has proven to be very safe for human consumption. Without modification, anti-DENV2 IgY can be rapidly produced and may serve as a good therapeutic option to treat dengue worldwide.
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影响因子：
6.7
作者：
Balsitis SJ;Williams KL;Lachica R;Flores D;Kyle JL;Mehlhop E;Johnson S;Diamond MS;Beatty PR;Harris E
通讯作者：
Harris E
影响因子：
3.8
作者：
Haese N;Brocato RL;Henderson T;Nilles ML;Kwilas SA;Josleyn MD;Hammerbeck CD;Schiltz J;Royals M;Ballantyne J;Hooper JW;Bradley DS
通讯作者：
Bradley DS
影响因子：
30.3
作者：
Beltramello M;Williams KL;Simmons CP;Macagno A;Simonelli L;Quyen NT;Sukupolvi-Petty S;Navarro-Sanchez E;Young PR;de Silva AM;Rey FA;Varani L;Whitehead SS;Diamond MS;Harris E;Lanzavecchia A;Sallusto F
通讯作者：
Sallusto F
影响因子：
5.4
作者：
Brien, James D.;Sukupolvi-Petty, Soila;Diamond, Michael S.
通讯作者：
Diamond, Michael S.
影响因子：
5.5
作者：
Ibrahim, El-Sayed Moustafa;Rahman, A. K. M. Shofiqur;Kodama, Yoshikatsu
通讯作者：
Kodama, Yoshikatsu