MedicalResearch.com Interview with:
Dr. Eng Eong Ooi BMBS PhD FRCPath
Associate Professor & Deputy Director
Program in Emerging Infectious Diseases
Duke-NUS Graduate Medical School
Medical Research: What is the background for this study? What are the main findings?
Response: Dengue prevention continues to rely exclusively on vector control guided by disease and virologic surveillance. The latter has focused on detecting changes in the prevalence of the four antigenically distinct viral serotypes as, in general terms, herd immunity depends on long-lived serotype-specific antibodies. However, epidemiological observations have indicated that a small number of changes within the viral genome have also been associated with several major outbreaks, without any change in viral serotype. Identifying the genetic changes that alter viral fitness epidemiologically would thus be important to differentiate strains that have a greater potential of causing epidemics and targeted for control.
Using the 1994 outbreak in Puerto Rico as a case in point, we identified nucleotide substitutions in the 3’ untranslated region (3’UTR) of the viral genome as critical determinants of dengue virus’ epidemiological fitness. Mechanistically, mutations in the 3’UTR altered secondary viral RNA structures and changed the relative proportion of genomic to subgenomic RNA of the virus in infected cells. The epidemiologically fitter viruses produced larger amounts of subgenomic to genomic RNA. This subgenomic RNA then binds a host protein, TRIM25, which is a E3 ubiquitin ligase that polyubiquitylates RIG-I to amplify and sustain signalling for type-I interferon expression. By binding to TRIM25, the subgenomic RNA of dengue virus inhibits the activation and thus enzymatic function of TRIM25. We suggest that with reduced interferon expression, the virus was thus able to spread more effectively from cell to cell within the infected individuals to reach viremia levels for further subsequent mosquito-borne transmission.
Medical Research: What should clinicians and patients take away from your report?
Response: Our work indicates that not all dengue viruses have the same potential for causing outbreaks. Identifying the genetic signatures that give rise to epidemiologically fitter viruses could enable us to refine our virologic surveillance from a serotype level information to one based on molecular evidence. Public health response to dengue could thus be triaged based on risk of epidemic emergence rather than the number of cases within specific locales. The latter often represents a response that is too little too late to stem an epidemic.
Medical Research: What recommendations do you have for future research as a result of this study?
Response: Besides identifying a determinant of epidemiological fitness, our work has also now provided a framework to investigate past outbreaks. Cataloging the genetic changes that affects dengue virus fitness in its epidemiological setting and how these changes are mediated mechanistically would be important if we are to bring virologic surveillance to a new level of accuracy in the future.
Manokaran, E. Finol, C. Wang, J. Gunaratne, J. Bahl, E. Z. Ong, H. C. Tan, O. M. Sessions, A. M. Ward, D. J. Gubler, E. Harris, M. A. Garcia-Blanco, E. E. Ooi. Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness. Science, 2015; DOI: 10.1126/science.aab3369
Dr. Eng Eong Ooi BMBS PhD FRCPath, & Associate Professor & Deputy Director (2015). Not All Dengue Viruses Have Have Same Potential For Disease Outbreaks