Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes
Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes
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DOI：
10.1073/pnas.2026027118
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发表时间：
2021-05-04
影响因子：
11.1
通讯作者：
Lee, Benhur
中科院分区：
文献类型：
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作者：
Ikegame, Satoshi;Hashiguchi, Takao;Lee, Benhur
麻疹病毒（MeV）在2019年死灰复燃，造成超过20万人死亡。MeV感染可导致大脑慢性潜伏感染，并可在原发性感染康复后数月至数年内复发。复发性MeV导致致命的亚急性硬化性全脑炎（SSPE）或麻疹包涵体脑炎（MIBE），因为病毒在多个大脑区域传播。SSPE/MIBE菌株的大多数临床分离株显示融合（F）基因突变，导致体外超灌注表型，并允许在原代人神经元中有效扩散。野生型MeV受体结合蛋白对于表现这些突变F表型是必不可少的，即使神经元缺乏典型MeV受体（CD 150/SLAMF 1或nectin-4）。如何选择这样的hyperfusogenic F突变体，以及它们是否赋予有效的神经元扩散的适应性优势还没有得到解决。为了更好地了解健身景观，允许选择这样的hyperfusogenic F突变体，我们进行了筛选？3.1 ? 105 MeV-F点突变体在其基因组背景下。我们在BSR-T7细胞中在MeV-F-T461 I（已知的SSPE突变体）而不是野生型MeV可以传播的条件下拯救并扩增了我们的基因组MeV-F突变体文库。我们回收了已知的SSPE突变体，但也表征了至少15个具有SSPE表型的超致突变F。这些突变体到融合前MeV-F三聚体的结构映射证实并扩展了我们对MeV-F中F调节结构域的理解。我们的超致流性F突变体的列表是一个宝贵的资源，为未来的研究兆电子伏神经发病机制和副粘病毒F的调节。
Measles virus (MeV) is resurgent and caused >200,000 deaths in 2019. MeV infection can establish a chronic latent infection of the brain that can recrudesce months to years after recovery from the primary infection. Recrudescent MeV leads to fatal subacute sclerosing panencephalitis (SSPE) or measles inclusion body encephalitis (MIBE) as the virus spreads across multiple brain regions. Most clinical isolates of SSPE/MIBE strains show mutations in the fusion (F) gene that result in a hyperfusogenic phenotype in vitro and allow for efficient spread in primary human neurons. Wild-type MeV receptor-binding protein is indispensable for manifesting these mutant F phenotypes, even though neurons lack canonical MeV receptors (CD150/SLAMF1 or nectin-4). How such hyperfusogenic F mutants are selected and whether they confer a fitness advantage for efficient neuronal spread is unresolved. To better understand the fitness landscape that allows for the selection of such hyperfusogenic F mutants, we conducted a screen of ?3.1 ? 105 MeV-F point mutants in their genomic context. We rescued and amplified our genomic MeV-F mutant libraries in BSR-T7 cells under conditions in which MeV-F-T461I (a known SSPE mutant), but not wild-type MeV, can spread. We recovered known SSPE mutants but also characterized at least 15 hyperfusogenic F mutations with an SSPE phenotype. Structural mapping of these mutants onto the prefusion MeV-F trimer confirm and extend our understanding of the F regulatory domains in MeV-F. Our list of hyperfusogenic F mutants is a valuable resource for future studies into MeV neuropathogenesis and the regulation of paramyxovirus F.