Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification.
Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification.
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DOI：
10.1371/journal.ppat.1000790
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发表时间：
2010-02-12
期刊：
影响因子：
6.7
通讯作者：
Harris E
中科院分区：
文献类型：
--
作者：
Balsitis SJ;Williams KL;Lachica R;Flores D;Kyle JL;Mehlhop E;Johnson S;Diamond MS;Beatty PR;Harris E
对四种登革热病毒（DV）血清型中的一种产生的免疫可能会在随后感染另一种DV血清型时增加人类疾病的严重程度。血清型交叉反应抗体通过促进病毒经由Fcγ受体（FcγR）进入，在体外促进DV对髓系细胞的感染，这一过程被称为抗体依赖增强作用（ADE）。然而，尽管经过了数十年的研究，却尚未有关于抗体增强登革热疾病严重程度的体内模型被描述。类似于通过胎盘转移获得抗DV抗体并在初次感染期间患上严重登革热疾病的人类婴儿，我们在此表明，使用适应小鼠的和临床的DV分离株，被动给予抗DV抗体足以增强小鼠的DV感染和疾病。抗体增强的致死性疾病具有人类严重登革热疾病的许多特征，包括血小板减少、血管渗漏、血清细胞因子水平升高以及血清和组织吞噬细胞中的全身病毒载量增加。高剂量的血清型特异性抗体的被动转移消除了病毒血症，但较低剂量的这些抗体或者交叉反应的多克隆或单克隆抗体在体内都会增强疾病，即使这些抗体在体外具有中和作用。相比之下，一种不能结合FcγR的基因工程抗体变体（E60 - N297Q）对ADE诱导的致死性攻击表现出预防和治疗功效。这些观察结果为抗体增强型登革热疾病的发病机制提供了见解，并确定了一种设计抗登革热治疗性抗体的新策略。
登革热是人类最常见的虫媒病毒性疾病，超过30亿人面临感染风险，热带和亚热带地区每年有5000万 - 1亿人感染。登革热病毒（DV）引起一系列临床疾病，从急性使人衰弱的自限性发热疾病（DF）到危及生命的血管渗漏综合征，即登革出血热/登革休克综合征（DHF/DSS）。登革热病毒有四种血清型；感染一种血清型被认为可防止再次感染同一血清型，但可能防止或增强对其他三种血清型中某一种的感染。流行病学和体外数据表明抗登革热病毒抗体在介导第二次登革热病毒感染的发病机制中起作用。然而，尚不清楚哪些抗体情况具有保护作用，哪些在体内会加重疾病，部分原因是没有可用的抗体增强型登革热疾病的动物模型。在此，我们提出了第一个抗体增强型严重登革热病毒感染的动物模型。重要的是，该模型重现了人类疾病的许多方面，包括血管渗漏、血清细胞因子水平升高、血小板计数减少以及组织吞噬细胞的播散性感染。此外，我们通过展示一种不能结合Fcγ受体的基因修饰的抗登革热病毒抗体在体内对致死性登革热病毒攻击具有预防和治疗功效，证明了该模型的实用性。
Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcγR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue. Dengue is the most common vector-borne viral disease of humans, with over 3 billion people at risk for infection and 50–100 million infections in tropical and subtropical regions each year. Dengue virus (DV) causes a spectrum of clinical disease ranging from an acute debilitating, self-limited febrile illness (DF) to a life-threatening vascular leakage syndrome, referred to as dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). There are four serotypes of DENV; infection with one serotype is thought to protect against re-infection with the same serotype, but may either protect against or enhance infection with one of the other three serotypes. Epidemiological and in vitro data has implicated anti-DENV antibodies in mediating pathogenesis of a second DENV infection. However, it is unclear which antibody conditions are protective and which exacerbate disease in vivo, in part because no animal model of antibody-enhanced dengue disease has been available. Here, we present the first animal model of antibody-enhanced severe DENV infection. Importantly, this model recapitulates many aspects of human disease, including vascular leakage, elevated serum cytokine levels, reduced platelet count, and disseminated infection of tissue phagocytes. Furthermore, we demonstrate the utility of this model by showing that a genetically modified anti-DENV antibody that fails to bind the Fcγ receptor has prophylactic and therapeutic efficacy against lethal DENV challenge in vivo.
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DOI：
10.1073/pnas.0703498104
发表时间：
2007-05-29
影响因子：
11.1
作者：
Goncalvez, Ana P.;Engle, Ronald E.;Lai, Ching-Juh
通讯作者：
Lai, Ching-Juh
影响因子：
3.7
作者：
Holden, KL;Stein, DA;Harris, E
通讯作者：
Harris, E
影响因子：
5.4
作者：
Boonnak, Kobporn;Slike, Bonnie M.;Marovich, Mary A.
通讯作者：
Marovich, Mary A.
DOI：
10.1086/590117
发表时间：
2008-08-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Chau TN;Quyen NT;Thuy TT;Tuan NM;Hoang DM;Dung NT;Lien le B;Quy NT;Hieu NT;Hieu LT;Hien TT;Hung NT;Farrar J;Simmons CP
通讯作者：
Simmons CP
影响因子：
5.4
作者：
Crill, WD;Chang, GJJ
通讯作者：
Chang, GJJ