Dengue Virus Infection with Highly Neutralizing Levels of Cross-Reactive Antibodies Causes Acute Lethal Small Intestinal Pathology without a High Level of Viremia in Mice
Dengue Virus Infection with Highly Neutralizing Levels of Cross-Reactive Antibodies Causes Acute Lethal Small Intestinal Pathology without a High Level of Viremia in Mice
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具有高中和水平交叉反应抗体的登革热病毒感染可导致小鼠急性致死性小肠病理，但不出现高水平病毒血症
DOI：
10.1128/jvi.00216-15
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发表时间：
2015
影响因子：
5.4
通讯作者：
S. Vasudevan
中科院分区：
文献类型：
--
作者：
Satoru Watanabe;K. W. Chan;Jiaqi Wang;L. Rivino;S. Lok;S. Vasudevan
摘要重症登革病毒（DENV）相关疾病可发生在已存在DENV抗体（Ab）的患者中，通过感染的抗体依赖性增强（ADE）。已充分确定，在ADE期间，DENV-抗体免疫复合物（IC）感染携带Fcγ受体的细胞，并增加可在血液中测量的全身病毒负荷。为了防止DENV血清型1至4的感染，必须引发强中和Ab以克服ADE的作用。在具有母体DENV抗体的婴儿中的临床观察或最近使用领先的四价登革热疫苗进行的II/III期临床试验表明，抗体中和与体内疾病预防之间缺乏相关性。在解决这一知识缺口时，我们发现，接种由血清型交叉反应性抗体形成的IC，这些抗体在体外被中和超过98%，促进了AG 129小鼠的高死亡率，即使峰值病毒血症低于直接病毒感染。这表明血清病毒血症水平并不总是与疾病严重程度相关。我们进一步证明，IC感染导致血管通透性增加，特别是在小肠中，伴随组织病毒载量和细胞因子产生增加，这可以被抗肿瘤坏死因子α（抗TNF-α）Ab抑制。流式细胞术分析发现IC接种增加了CD 11bint CD 11 cint/hi CD 103 −抗原呈递细胞的感染，这表明这些感染的细胞可能是导致小鼠死亡的小肠TNF-α产生和血管通透性增加的原因。我们的发现可能对登革热治疗方法的发展具有重要意义。重要性我们在小鼠模型中检查了感染时Ab中和水平与随后疾病进展之间的关系，以理解为什么显示具有中和量Ab的患者仍然允许足够的DENV复制以诱导严重的登革热表现，这有时与病毒血症水平无关。引人注目的是，我们发现，即使初始感染水平被抑制至低于5%且峰值病毒血症水平未增强，TNF-α诱导的血管通透性增加伴随病毒载量增加（特别是在小肠中），在AG 129小鼠中诱导了高死亡率。这表明ADE以组织依赖性方式克服了Ab的保护功效，导致严重的小肠病理学。我们的研究结果可能有助于解决抗体对严重登革热疾病的致病作用，也有助于开发安全的抗体为基础的治疗策略。
ABSTRACT Severe dengue virus (DENV)-associated diseases can occur in patients who have preexisting DENV antibodies (Abs) through antibody-dependent enhancement (ADE) of infection. It is well established that during ADE, DENV-antibody immune complexes (ICs) infect Fcγ receptor-bearing cells and increase the systemic viral burden that can be measured in the blood. For protection against infection with DENV serotypes 1 to 4, strongly neutralizing Abs must be elicited to overcome the effect of ADE. Clinical observations in infants who have maternal DENV Abs or recent phase II/III clinical trials with a leading tetravalent dengue vaccine suggested a lack of correlation between Ab neutralization and in vivo disease prevention. In addressing this gap in knowledge, we found that inoculation of ICs formed with serotype cross-reactive Abs that are more than 98% neutralized in vitro promotes high mortality in AG129 mice even though peak viremia was lower than that in direct virus infection. This suggests that the serum viremia level is not always correlated with disease severity. We further demonstrated that infection with the ICs resulted in increased vascular permeability, specifically in the small intestine, accompanied with increased tissue viral load and cytokine production, which can be suppressed by anti-tumor necrosis factor alpha (anti-TNF-α) Abs. Flow cytometric analysis identified increased infection in CD11bint CD11cint/hi CD103− antigen-presenting cells by IC inoculation, suggesting that these infected cells may be responsible for the increase in TNF-α production and vascular permeability in the small intestine that lead to mortality in mice. Our findings may have important implications for the development of dengue therapeutics. IMPORTANCE We examined the relationship between the neutralizing level of Abs at the time of infection and subsequent disease progression in a mouse model in order to understand why patients who are shown to have a neutralizing quantity of Abs still allow sufficient DENV replication to induce severe dengue manifestations, which sometimes do not correlate with viremia level. Strikingly, we found that high mortality was induced in AG129 mice by the increase in TNF-α-induced vascular permeability accompanied by an increased viral load, specifically in the small intestine, even when the initial infection level is suppressed to less than 5% and the peak viremia level is not enhanced. This suggests that ADE overcomes the protective efficacy of Abs in a tissue-dependent manner that leads to severe small intestinal pathology. Our findings may serve to address the pathogenic role of Abs on severe dengue disease and also help to develop safe Ab-based therapeutic strategies.
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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：
6.4
作者：
Libraty, DH;Young, PR;Rothman, AL
通讯作者：
Rothman, AL
影响因子：
6.4
作者：
Vaughn, DW;Green, S;Nisalak, A
通讯作者：
Nisalak, A
影响因子：
6.4
作者：
Libraty, DH;Endy, TP;Rothman, AL
通讯作者：
Rothman, AL