A prM mutation that attenuates dengue virus replication in human cells enhances midgut infection in mosquitoes

• Published in: Science translational medicine 2024-07, Vol.16 (758), p.eadk4769
• Main Authors: Choi, Allyson N X, Siriphanitchakorn, Tanamas, Choy, Milly M, Ooi, Justin S G, Manuel, Menchie, Tan, Hwee Cheng, Lin, Lowell Z, Yap, Xin, Gubler, Duane J, Ooi, Eng Eong
• Format: Article
• Language: English
• Subjects: Aedes - virology; Animals; Cell Line; Dengue - transmission; Dengue - virology; Dengue fever; Dengue Virus - genetics; Dengue Virus - physiology; Disease transmission; Epidemics; Epidemiology; Histidine; Humans; Islands; Mammalian cells; Midgut; Mutation; Mutation - genetics; Outbreaks; Phylogeny; Protein Biosynthesis; Replication; Translation; Virus Replication - genetics; Viruses
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.adk4769

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 . 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.