Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness

Gayathri Manokaran(National University of Singapore), Esteban Finol(Swiss Tropical and Public Health Institute), Chunling Wang(University of California, Berkeley), Jayantha Gunaratne(National University of Singapore), Justin Bahl, Eugenia Z. Ong(National University of Singapore), Hwee Cheng Tan(National University of Singapore), October M. Sessions(National University of Singapore), Alex M. Ward(National University of Singapore), Duane J. Gubler(National University of Singapore), Eva Harris(University of California, Berkeley), Mariano A. García-Blanco(National University of Singapore), Eng Eong Ooi(National University of Singapore)
Science
July 3, 2015
10.1126/science.aab3369
Cited by 419

Abstract

The global spread of dengue virus (DENV) infections has increased viral genetic diversity, some of which appears associated with greater epidemic potential. The mechanisms governing viral fitness in epidemiological settings, however, remain poorly defined. We identified a determinant of fitness in a foreign dominant (PR-2B) DENV serotype 2 (DENV-2) clade, which emerged during the 1994 epidemic in Puerto Rico and replaced an endemic (PR-1) DENV-2 clade. The PR-2B DENV-2 produced increased levels of subgenomic flavivirus RNA (sfRNA) relative to genomic RNA during replication. PR-2B sfRNA showed sequence-dependent binding to and prevention of tripartite motif 25 (TRIM25) deubiquitylation, which is critical for sustained and amplified retinoic acid-inducible gene 1 (RIG-I)-induced type I interferon expression. Our findings demonstrate a distinctive viral RNA-host protein interaction to evade the innate immune response for increased epidemiological fitness.

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