Anti-Severe Acute Respiratory Syndrome Coronavirus Spike Antibodies Trigger Infection of Human Immune Cells via a pH-and Cysteine Protease-Independent FcγR Pathway
Anti-Severe Acute Respiratory Syndrome Coronavirus Spike Antibodies Trigger Infection of Human Immune Cells via a pH-and Cysteine Protease-Independent FcγR Pathway
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DOI：
10.1128/jvi.00671-11
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发表时间：
2011-10-01
影响因子：
5.4
通讯作者：
Peiris, J. S. Malik
中科院分区：
文献类型：
--
作者：
Jaume, Martial;Yip, Ming S.;Peiris, J. S. Malik
公共卫生措施成功控制了严重急性呼吸系统综合征冠状病毒感染的爆发。然而，SARS-CoV的前体仍然存在于其天然的蝙蝠宿主中，并且人类适应的SARS样冠状病毒的重新出现仍然是一个合理的公共卫生问题。接种疫苗是控制SARS在人类中复发的主要策略，许多候选疫苗已经在实验动物模型中进行了测试。我们先前报道了基于重组全长刺突蛋白三聚体的SARS-CoV候选疫苗引起的抗体增强了人B细胞系的感染，尽管在啮齿动物体内引起中和和保护性免疫应答。这些观察结果促使我们在体外研究SARS-CoV感染的抗体依赖性增强（ADE）的机制。我们在这里证明，抗刺突免疫血清，同时抑制病毒进入一个允许的细胞系，增强免疫细胞的感染SARS-CoV刺突假型慢病毒颗粒，以及复制能力的SARS冠状病毒。抗体介导的感染依赖于Fc γ受体II，但不使用血管紧张素I转化酶2（ACE 2）（SARS-CoV的公认受体）所利用的内体/溶酶体途径。这表明SARS-CoV的ADE利用了一种新的细胞进入免疫细胞的机制。不同的SARS候选疫苗引起的血清在免疫细胞中诱导ADE的能力不同，尽管它们在携带ACE 2的细胞中中和感染的效力相当。我们的研究结果提示了SARS冠状病毒进入靶细胞的一种新机制，并阐明了与免疫相关的潜在缺陷。这些发现将促进对SARS发病机制的进一步研究。
Public health measures successfully contained outbreaks of the severe acute respiratory syndrome coronavirus (SARS-CoV) infection. However, the precursor of the SARS-CoV remains in its natural bat reservoir, and reemergence of a human-adapted SARS-like coronavirus remains a plausible public health concern. Vaccination is a major strategy for containing resurgence of SARS in humans, and a number of vaccine candidates have been tested in experimental animal models. We previously reported that antibody elicited by a SARS-CoV vaccine candidate based on recombinant full-length Spike-protein trimers potentiated infection of human B cell lines despite eliciting in vivo a neutralizing and protective immune response in rodents. These observations prompted us to investigate the mechanisms underlying antibody-dependent enhancement (ADE) of SARS-CoV infection in vitro. We demonstrate here that anti-Spike immune serum, while inhibiting viral entry in a permissive cell line, potentiated infection of immune cells by SARS-CoV Spike-pseudotyped lentiviral particles, as well as replication-competent SARS coronavirus. Antibody-mediated infection was dependent on Fc gamma receptor II but did not use the endosomal/lysosomal pathway utilized by angiotensin I converting enzyme 2 (ACE2), the accepted receptor for SARS-CoV. This suggests that ADE of SARS-CoV utilizes a novel cell entry mechanism into immune cells. Different SARS vaccine candidates elicit sera that differ in their capacity to induce ADE in immune cells despite their comparable potency to neutralize infection in ACE2-bearing cells. Our results suggest a novel mechanism by which SARS-CoV can enter target cells and illustrate the potential pitfalls associated with immunization against it. These findings should prompt further investigations into SARS pathogenesis.