Mutations in the 3'UTR of dengue virus modulate innate immune responses in primary human systems.

REBECCA HAMLIN; SEBASTIAN AGUIRRE; CLAUDIA FILOMATORI; SERGIO VILLORDO; DABEIBA BERNAL-RUBIO; RAYMOND ALVAREZ; MICHAEL DONOVAN; ANDREA GAMARNIK; ANA FERNANDEZ-SESMA

New Orleans

Congreso; 63nd Annual Meeting of the American Society of Tropical Medicine and Hygiene; 2014

The American Society of Tropical Medicine and Hygiene

Dengue virus (DENV) is an important human pathogen transmitted to humans by a mosquito vector with an estimated 390 million infections per year worldwide; there are currently no licensed vaccines or specific therapeutics, and the death rate for severe dengue without proper supportive care can be over 20%. Hematopoietic cells like dendritic cells (DCs), monocytes, and macrophages are believed to be the primary targets of DENV infection, replication, and dissemination. To efficiently infect humans, DENV must evade or inhibit elements of the innate immune system. Indeed, wild type (WT) DENV infection has been shown by our group and others to inhibit both type I interferon (IFN alfa and beta) production and signaling. In collaboration with the Gamarnik laboratory, we have started to analyze the immune response in human DCs infected with a panel of recombinant DENV with specific deletions in the 3´ untranslated region (UTR) of the viral genome. We have found that there was higher induction of type I IFN and the IFN stimulated genes (ISG) IP-10 in DCs infected with DENV with mutations in the 3´UTR, such as the delta 30 deletion featured in the NIH/NIAID vaccine candidates, compared to WT DENV-2 infection. These data suggest that alterations in the UTR may influence the ability of DENV to be sensed by innate immune sensors. We have also examined infection of WT DENV and these mutant viruses in a newly developed, human tonsil histoculture model system. Our preliminary data show that these DENV can replicate in these tissues and induce distinct phenotypes in this system that are comparable to those observed in human DCs.