University of Texas Medical Branch, Galveston, Texas, USA
Boston University, Boston, Massachusetts, USA.
J Virol. 2020 Mar 31;94(8). doi: 10.1128/JVI.01693-19.
Argentine hemorrhagic fever is a potentially lethal disease that is caused by Junin virus (JUNV). There are currently around 5 million individuals at risk of infection within regions of endemicity in Argentina. The live attenuated vaccine strain Candid #1 (Can) is approved for use in regions of endemicity and has substantially decreased the number of annual Argentine hemorrhagic fever (AHF) cases. The glycoprotein (GPC) gene is primarily responsible for attenuation of the Can strain, and we have shown that the absence of an -linked glycosylation motif in the subunit G1 of the glycoprotein complex of Can, which is otherwise present in the wild-type pathogenic JUNV, causes GPC retention in the endoplasmic reticulum (ER). Here, we show that Can GPC aggregates in the ER of infected cells, forming incorrect cross-chain disulfide bonds, which results in impaired GPC processing into G1 and G2. The GPC fails to cleave into its G1 and G2 subunits and is targeted for degradation within lysosomes. Cells infected with the wild-type Romero (Rom) strain do not produce aggregates that are observed in Can infection, and the stress on the ER remains minimal. While the mutation of the -linked glycosylation motif (T168A) is primarily responsible for the formation of aggregates, other mutations within G1 that occurred earlier in the passage history of the Can strain also contribute to aggregation of the GPC within the ER. The development of vaccines and therapeutics to combat viral hemorrhagic fevers remains a top priority within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. The Can strain, derived from the pathogenic XJ strain of JUNV, has been demonstrated to be both safe and protective against AHF. While the vaccine strain is approved for use in regions of endemicity within Argentina, the mechanisms of Can attenuation have not been elucidated. A better understanding of the viral genetic determinants of attenuation will improve our understanding of the mechanisms contributing to disease pathogenesis and provide critical information for the rational design of live attenuated vaccine candidates for other viral hemorrhagic fevers.
阿根廷出血热是一种潜在致命的疾病，由胡宁病毒（JUNV）引起。目前，在阿根廷流行地区，约有 500 万人面临感染风险。活减毒疫苗株 Candid #1（Can）在流行地区获准使用，并大大减少了每年阿根廷出血热（AHF）的病例数。糖蛋白（GPC）基因主要负责 Can 株的减毒，我们已经表明，Can 糖蛋白复合物亚基 G1 中不存在 -连接糖基化模体，而野生型致病性 JUNV 中存在该模体，导致 GPC 在内质网（ER）中滞留。在这里，我们表明 Can GPC 在感染细胞的 ER 中聚集，形成错误的交叉链二硫键，导致 GPC 加工成 G1 和 G2 受损。GPC 未能裂解成其 G1 和 G2 亚基，并在溶酶体中被靶向降解。感染野生型 Romero（Rom）株的细胞不会产生在 Can 感染中观察到的聚集物，内质网的压力仍然很小。虽然 -连接糖基化模体（T168A）的突变主要负责形成聚集物，但 Can 株传代史早期发生的 G1 中的其他突变也导致 GPC 在 ER 内聚集。制定疫苗和治疗方法来对抗病毒性出血热仍然是美国卫生与公众服务部公共卫生应急医疗对策企业实施计划的重中之重。Can 株源自 JUNV 的致病性 XJ 株，已被证明既安全又能预防 AHF。虽然疫苗株已获准在阿根廷流行地区使用，但 Can 减毒的机制尚未阐明。更好地了解病毒遗传决定因素的衰减将有助于我们了解导致疾病发病机制的机制，并为其他病毒性出血热的活减毒疫苗候选物的合理设计提供关键信息。
