Structure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic Potential.
Structure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic Potential.
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DOI：
10.1128/jvi.01248-18
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发表时间：
2018-12-01
影响因子：
5.4
通讯作者：
Bailey D
中科院分区：
文献类型：
--
作者：
Abdullah N;Kelly JT;Graham SC;Birch J;Gonçalves-Carneiro D;Mitchell T;Thompson RN;Lythgoe KA;Logan N;Hosie MJ;Bavro VN;Willett BJ;Heaton MP;Bailey D
很大一部分病毒大流行发生在人畜共患传播事件之后，即动物相关病毒跨物种进入人群。为了提供这些病毒出现的预警，有必要更好地了解决定病毒宿主范围的因素，通常是在遗传和结构水平上。在这项研究中，我们证明了麻疹的近亲小反刍动物麻疹病毒不能利用人类受体进入细胞；然而，病毒中单个氨基酸的改变就足以克服这一限制。这一信息对于在现场监测该病毒的演变将是重要的。值得注意的是，这项研究是在体外进行的，没有产生具有这种表型的完全感染性病毒。麻疹病毒感染范围广泛的哺乳动物宿主，包括反刍动物、食肉动物和人类。最近根除牛瘟病毒（RPV）和积极根除人类特异性麻疹病毒（MeV）的运动引起了人们的严重关切，即剩余的麻疹病毒可能会在所谓的空出的生态位中出现。为了评估非人类麻疹病毒在人群中的人畜共患潜力，我们发现小反刍动物鼠疫病毒（PPRV）——小反刍动物麻疹病毒——由于缺乏与人类麻疹病毒免疫细胞受体slamf1的相互作用，在进入人类细胞时受到限制。使用结构引导方法，我们表征了单个氨基酸变化，映射到PPRV血凝素(H)蛋白的受体结合域，从而克服了这一限制。同样的突变允许从一些交叉保护的人类患者抗mev抗体中逃逸，这引起了人们对PPRV是一种具有人畜共患潜力的病原体的担忧。对人类和羊SLAMF1自然变异的分析也发现了可能与抗病相关的多态性。最后，我们还研究了PPRV限制性的机制，确定了PPRV H与人SLAMF1蛋白之间的电荷不相容和空间位阻。重要的是，这项研究完全是通过替代病毒进入试验进行的，否定了原位衍生嗜人PPRV的要求，并阐明了鉴定病毒病原体中功能获得突变的替代策略。重要意义：很大一部分病毒大流行发生在人畜共患传播事件之后，即动物相关病毒跨物种进入人群。为了提供这些病毒出现的预警，有必要更好地了解决定病毒宿主范围的因素，通常是在遗传和结构水平上。在这项研究中，我们证明了麻疹的近亲小反刍动物麻疹病毒不能利用人类受体进入细胞；然而，病毒中单个氨基酸的改变就足以克服这一限制。这一信息对于在现场监测该病毒的演变将是重要的。值得注意的是，这项研究是在体外进行的，没有产生具有这种表型的完全感染性病毒。
A significant proportion of viral pandemics occur following zoonotic transmission events, where animal-associated viruses jump species into human populations. In order to provide forewarnings of the emergence of these viruses, it is necessary to develop a better understanding of what determines virus host range, often at the genetic and structural levels. In this study, we demonstrated that the small-ruminant morbillivirus, a close relative of measles, is unable to use human receptors to enter cells; however, a change of a single amino acid in the virus is sufficient to overcome this restriction. This information will be important for monitoring this virus’s evolution in the field. Of note, this study was undertaken in vitro, without generation of a fully infectious virus with this phenotype. Morbilliviruses infect a broad range of mammalian hosts, including ruminants, carnivores, and humans. The recent eradication of rinderpest virus (RPV) and the active campaigns for eradication of the human-specific measles virus (MeV) have raised significant concerns that the remaining morbilliviruses may emerge in so-called vacated ecological niches. Seeking to assess the zoonotic potential of nonhuman morbilliviruses within human populations, we found that peste des petits ruminants virus (PPRV)—the small-ruminant morbillivirus—is restricted at the point of entry into human cells due to deficient interactions with human SLAMF1—the immune cell receptor for morbilliviruses. Using a structure-guided approach, we characterized a single amino acid change, mapping to the receptor-binding domain in the PPRV hemagglutinin (H) protein, which overcomes this restriction. The same mutation allowed escape from some cross-protective, human patient, anti-MeV antibodies, raising concerns that PPRV is a pathogen with zoonotic potential. Analysis of natural variation within human and ovine SLAMF1 also identified polymorphisms that could correlate with disease resistance. Finally, the mechanistic nature of the PPRV restriction was also investigated, identifying charge incompatibility and steric hindrance between PPRV H and human SLAMF1 proteins. Importantly, this research was performed entirely using surrogate virus entry assays, negating the requirement for in situ derivation of a human-tropic PPRV and illustrating alternative strategies for identifying gain-of-function mutations in viral pathogens. IMPORTANCE A significant proportion of viral pandemics occur following zoonotic transmission events, where animal-associated viruses jump species into human populations. In order to provide forewarnings of the emergence of these viruses, it is necessary to develop a better understanding of what determines virus host range, often at the genetic and structural levels. In this study, we demonstrated that the small-ruminant morbillivirus, a close relative of measles, is unable to use human receptors to enter cells; however, a change of a single amino acid in the virus is sufficient to overcome this restriction. This information will be important for monitoring this virus’s evolution in the field. Of note, this study was undertaken in vitro, without generation of a fully infectious virus with this phenotype.