Dengue viruses (DENVs), like all viruses, evolve to perpetuate transmission of their species in their hosts. However, how DENV genetics influences dengue disease outbreaks remains poorly understood. Here, we examined isolates of the South Pacific dengue virus type 2 (DENV-2) that emerged in the 1970s and caused major dengue outbreaks in islands in this region until it reached Tonga, where only a few mild cases were reported. Phylogenetically, the DENV-2 strain isolated in Tonga segregated into a clade different from those clades infecting populations in other South Pacific islands. We found that this epidemiological observation could be explained by a single histidine-to-arginine substitution in position 86 of the premembrane (prM) protein of the Tonga DENV-2 strain. This mutation attenuated viral protein translation in mammalian cells but not in midgut cells of the mosquito vector Aedes aegypti . In mammalian cells, the prM mutation resulted in reduced translation of the viral genome and subsequent reduced virus replication. In contrast, in mosquito midgut cells, the prM mutation conferred a selective infection advantage, possibly because of the positively charged arginine residue introduced by the mutation. These findings provide molecular insights into the year-long silent transmission of attenuated DENV-2 in Tonga during the 1970s dengue outbreak in the South Pacific.

中文翻译：

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prM突变可减弱登革热病毒在人类细胞中的复制，从而增强蚊子的中肠感染


与所有病毒一样，登革热病毒 (DENV) 也会进化以在宿主体内永久传播其物种。然而，人们对登革热病毒遗传学如何影响登革热疫情的了解仍知之甚少。在这里，我们检测了 2 型南太平洋登革热病毒 (DENV-2) 的分离株，该病毒出现于 20 世纪 70 年代，在该地区的岛屿上引发了大规模登革热疫情，直到传播到汤加，而汤加只报告了少数轻微病例。从系统发育上看，在汤加分离的 DENV-2 菌株分离成一个与感染其他南太平洋岛屿群体的进化枝不同的进化枝。我们发现这种流行病学观察结果可以通过汤加 DENV-2 毒株前膜 (prM) 蛋白第 86 位的单一组氨酸替换为精氨酸来解释。这种突变减弱了哺乳动物细胞中病毒蛋白的翻译，但在蚊媒埃及伊蚊的中肠细胞中却没有减弱。在哺乳动物细胞中，prM 突变导致病毒基因组翻译减少，进而导致病毒复制减少。相比之下，在蚊子中肠细胞中，prM 突变赋予了选择性感染优势，可能是因为该突变引入了带正电荷的精氨酸残基。这些发现为 20 世纪 70 年代南太平洋登革热爆发期间减毒 DENV-2 在汤加长达一年的无声传播提供了分子见解。