Competitive suppression of dengue viruses – Survival of the fittest

Abstract

Background: Dengue/severe dengue is an emerging threat to global health. Selective pressures, such as the host immune response or environmental changes might favour expansion of certain dengue virus (DENV) serotype/s or strains over others. The constant co-circulation of all four DENV serotypes may contribute to competition between strains that may result in increased competence of some serotypes or strains relative to others. Methods and materials: We have analyzed mono-infections, co-infections and super-infections using different dengue virus (DENV) serotypes to define DENV dynamics, competition and displacement. The current in vitro experimental design using C6/36 cells mimics the natural competition occurring among different DENV serotypes in the Aedes mosquito vectors in dengue affected regions. Results: In mono infection experiments in C6/36 cells, DENV-2 infection showed the highest viral titre followed by DENV-4, DENV-3 and DENV-1. In co-infection experiments in C6/36 cells, DENV-1 showed low viral titre when it was co-infected with DENV-2 or DENV-3. DENV-4 was suppressed by DENV-1 during co-infection. DENV-4 showed low titres when co-infected with DENV-3. DENV-2 showed low viral titre when it was co-infected with DENV-3 or DENV-4. In super infection experiments in C6/36 cells, DENV-1 was unable to produce high viral titres in the presence of DENV-2 or DENV-3 irrespective of the infection order or timing of the super-infection interval. Once DENV-2 and DENV-3 infections have been established, it appears to be difficult for DENV-1 to replicate. The order of challenge with different serotypes during super-infection did not affect the outcomes for DENV-2 and DENV-3 as these viruses co-replicated without interfering each other. The order of infection was important for DENV-1 and -4 challenges. Infection with DENV-1 followed by DENV-4 resulted in high DENV-4 titres while infection with DENV-4 first followed by DENV-1 led to high DENV-1 titres. Conclusion: Current results support the establishment of the predominance of a particular DENV serotype/sin co-infection and super-infection models tested in the laboratory. Moreover, DENV replication in co-infection and super-infection models provides understanding on virus transmission and stability at a particular time and location through competition and interactions between different DENV serotypes. Future studies in primate cells will define if similar interference occurs in mammalian hosts.