Structures of Two Human Astrovirus Capsid/Neutralizing Antibody Complexes Reveal Distinct Epitopes and Inhibition of Virus Attachment to Cells.
Structures of Two Human Astrovirus Capsid/Neutralizing Antibody Complexes Reveal Distinct Epitopes and Inhibition of Virus Attachment to Cells.
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DOI：
10.1128/jvi.01415-21
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发表时间：
2022-01-12
影响因子：
5.4
通讯作者：
DuBois RM
中科院分区：
文献类型：
--
作者：
Ricemeyer L;Aguilar-Hernández N;López T;Espinosa R;Lanning S;Mukherjee S;Cuellar C;López S;Arias CF;DuBois RM
人类星状病毒是世界范围内病毒性胃肠炎的重要病因。幼儿、老年人和免疫功能低下者特别容易感染严重疾病。然而，目前还没有对抗人类星状病毒感染的疫苗。有证据表明抗体在保护健康成人免受再次感染方面的重要性。为了开发一种有效的亚单位疫苗，广泛地保护不同的星状病毒血清型，我们必须了解中和抗体如何在分子水平上靶向衣壳表面。在这里，我们报道了人类星状病毒衣壳刺突结构域与两个中和单克隆抗体结合的结构。这些抗体在刺突表面结合两个不同的构象表位。我们补充了现有的证据，即人类星状病毒衣壳刺突包含一个受体结合域，并证明这两种抗体通过阻断病毒对宿主细胞的附着来中和人类星状病毒。我们确定了重叠或毗邻抗体表位的保守氨基酸斑块，可能构成受体结合位点。我们的发现为开发预防和治疗人类星状病毒胃肠炎的疗法提供了基础。人类星状病毒在儿童时期几乎感染世界上的每个人，并引起腹泻、呕吐和发烧。尽管这种病毒很流行，但人们对抗体如何阻断星状病毒感染知之甚少。在这里，我们确定了星状病毒衣壳蛋白与两种病毒中和抗体复合物的晶体结构。我们发现抗体与衣壳刺突结构域上的两个不同位点结合，然而，这两种抗体都阻止病毒附着在人类细胞上。重要的是，我们的研究结果支持将人类星状病毒衣壳刺突作为亚基疫苗中的抗原来预防星状病毒疾病。
Human astrovirus is an important cause of viral gastroenteritis worldwide. Young children, the elderly, and the immunocompromised are especially at risk for contracting severe disease. However, no vaccines exist to combat human astrovirus infection. Evidence points to the importance of antibodies in protecting healthy adults from reinfection. To develop an effective subunit vaccine that broadly protects against diverse astrovirus serotypes, we must understand how neutralizing antibodies target the capsid surface at the molecular level. Here, we report the structures of the human astrovirus capsid spike domain bound to two neutralizing monoclonal antibodies. These antibodies bind two distinct conformational epitopes on the spike surface. We add to existing evidence that the human astrovirus capsid spike contains a receptor-binding domain and demonstrate that both antibodies neutralize human astrovirus by blocking virus attachment to host cells. We identify patches of conserved amino acids which overlap or border the antibody epitopes and may constitute a receptor-binding site. Our findings provide a basis for developing therapies to prevent and treat human astrovirus gastroenteritis. IMPORTANCE Human astroviruses infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. Despite the prevalence of this virus, little is known about how antibodies block astrovirus infection. Here, we determined the crystal structures of the astrovirus capsid protein in complex with two virus-neutralizing antibodies. We show that the antibodies bind to two distinct sites on the capsid spike domain, however, both antibodies block virus attachment to human cells. Importantly, our findings support the use of the human astrovirus capsid spike as an antigen in a subunit-based vaccine to prevent astrovirus disease.