Department of Pathology, University of Texas Medical Branch at Galveston, Texas, United States of America.
Department of Microbiology, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS Pathog. 2021 Mar 1;17(3):e1009356. doi: 10.1371/journal.ppat.1009356. eCollection 2021 Mar.
Several arenaviruses cause hemorrhagic fevers in humans with high case fatality rates. A vaccine named Candid#1 is available only against Junin virus (JUNV) in Argentina. Specific N-linked glycans on the arenavirus surface glycoprotein (GP) mask important epitopes and help the virus evade antibody responses. However the role of GPC glycans in arenavirus pathogenicity is largely unclear. In a lethal animal model of hemorrhagic fever-causing Machupo virus (MACV) infection, we found that a chimeric MACV with the ectodomain of GPC from Candid#1 vaccine was partially attenuated. Interestingly, mutations resulting in acquisition of N-linked glycans at GPC N83 and N166 frequently occurred in late stages of the infection. These glycosylation sites are conserved in the GPC of wild-type MACV, indicating that this is a phenotypic reversion for the chimeric MACV to gain those glycans crucial for infection in vivo. Further studies indicated that the GPC mutant viruses with additional glycans became more resistant to neutralizing antibodies and more virulent in animals. On the other hand, disruption of these glycosylation sites on wild-type MACV GPC rendered the virus substantially attenuated in vivo and also more susceptible to antibody neutralization, while loss of these glycans did not affect virus growth in cultured cells. We also found that MACV lacking specific GPC glycans elicited higher levels of neutralizing antibodies against wild-type MACV. Our findings revealed the critical role of specific glycans on GPC in arenavirus pathogenicity and have important implications for rational design of vaccines against this group of hemorrhagic fever-causing viruses.
几种沙粒病毒可引起人类出血性发热，死亡率很高。阿根廷有一种名为 Candid#1 的疫苗，仅针对胡宁病毒（JUNV）。沙粒病毒表面糖蛋白（GP）上的特定 N 连接聚糖掩盖了重要的表位，有助于病毒逃避抗体反应。然而，GPC 糖基在沙粒病毒致病性中的作用在很大程度上尚不清楚。在导致出血性发热的马丘波病毒（MACV）感染的致死性动物模型中，我们发现，具有 Candid#1 疫苗外域的嵌合 MACV 部分减毒。有趣的是，导致在感染后期获得 GPC N83 和 N166 上 N 连接聚糖的突变经常发生。这些糖基化位点在野生型 MACV 的 GPC 中保守，表明这是嵌合 MACV 为获得体内感染所需的那些糖基而发生的表型回复。进一步的研究表明，具有额外聚糖的 GPC 突变病毒对中和抗体更具抗性，在动物中更具毒力。另一方面，破坏野生型 MACV GPC 上的这些糖基化位点会使病毒在体内显著减毒，并且更容易被抗体中和，而这些糖基的缺失不会影响病毒在培养细胞中的生长。我们还发现，缺乏特定 GPC 聚糖的 MACV 可引发针对野生型 MACV 的更高水平的中和抗体。我们的研究结果揭示了 GPC 上特定聚糖在沙粒病毒致病性中的关键作用，对针对这组引起出血性发热的病毒的合理疫苗设计具有重要意义。
