Recognition of Dengue virus (DENV) by primary human dendritic cells and the inhibition of type I interferon production during infection.

SEBASTIAN AGUIRRE; ANA MAESTRE; SARAH PAGNI; DABEIBA BERNAL- RUBIO; CLAUDIA FILOMATORI; GLEN BARBER; ANDREA GAMARNIK; ANA FERNANDEZ-SESMA

Wisconsin-Madison

Congreso; XXXI Annual Meeting of the American Society for Virology; 2012

American Society for Virology

Dengue virus (DENV) is a blood pathogen with a high impact in human health that replicates in a wide range of cells involved in the immune response. To efficiently infect humans, DENV must evade or inhibit fundamental elements of the innate immune system, namely the type I interferon response. The production of these important antiviral cytokines is initiated upon detection of pathogens associated molecular patterns (PAMP´s) by the cellular pattern recognition receptors (PRRs). DENV can circumvent the host immune response using both, a passive scape strategy, hiding its replication products from the host PRRs, and also in an active fashion, expressing proteins that antagonize the cellular innate immunity. The main mechanism of immune evasion by this virus, described by several groups, is the interference of the type I IFN signaling pathway. Our laboratory has documented the inhibition of type I IFN production in human monocyte derived dendritic cells (MDDCs), with an otherwise strong cytokine and chemokine profile in those cells (Rodriguez-Madoz et al. J Virol 2010a). On a subsequent report we demonstrated that the NS2B3 protease complex of DENV functions as an antagonist of type I IFN production, and its proteolytic activity is necessary for this event (Rodriguez-Madoz et al. J Virol 2010b). In the present report we identify the human adaptor molecule STING as a target of the NS2B3 protease complex and characterize the mechanism of inhibition of the type I IFN production in primary human MDDCs mediated by this viral factor. We also describe that DENV NS2B3 cannot degrade the mouse version of STING, a phenomenon that strictly restricts the replication of DENV in mouse cells, suggesting that STING plays a key role in the inhibition of DENV infection and spread in mice. Additionally, we are analyzing the immune response in human DC´s, using a series of deletion mutants of the 3´untranslated (UTR) region of DENV. Preliminary results show that specific deletions in this region that have been shown to affect replication (Alvarez et al. Virology, 2005) may also confer a rearrangement of the viral RNA structures that could be sensed differently by the cellular PRRs,and affect viral detection by antigen presenting cells such as the ones described for other pathogens.