Dengue virus (DENV) is one of the most important human pathogen that affects millions of people in tropical areas of the world, and it is becoming increasingly present in non-tropical areas. DENV is transmitted by mosquitoes and can cause Dengue fever (DF) and Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS). Currently there are no vaccines or antivirals available for DENV and there is no immune competent animal model available to study this important disease. Our group was the first to report that DENV inhibits the production of type I interferon (IFN) in infected cells and this inhibition is mediated by the NS2B3 protease and allows for efficient infection by the virus. We then reported that the NS2B3 cleaves the immune adaptor molecule STING in permissive human primary cells. Interestingly, murine STING is uncleavable by the NS2B3 protease, making this innate immunity adaptor molecule a strong restriction factor for DENV infection in mice. Taking advantage of the data and resources that we generated during our first funding period we will further investigate host factors implicated in DENV sensing in infected cells. We will also identify host and viral factors important for immune evasion by DENV in infected cels. Finally we will develop new mouse models to study Dengue disease based on the restriction factor STING, by generating mice knocked in for human STING, which is susceptible to cleavage by the DENV NS2B3 protease and may prove to be more susceptible to DENV infection. If successful, this will constitute a potential immune competent new mouse model for DENV. We will use relevant DENV primary isolates of all four serotypes with known epidemic histories and sequences as well as recombinant DENV with specific mutations in viral innate immune antagonists and in RNA structures important for immune sensing, such as the current NIAID DENV vaccine prototypes. This application has the potential of developing the first immune competent mouse model to study DENV disease. We will also identify important factors that enable DENV infection in human systems, which could be targeted by antiviral drugs that could interfere with the virus-host interaction, such as the cleavage of STING by the DENV protease NS2B3.

Public Health Relevance

DENV is the most important human arthropod borne virus affecting millions of people worldwide;at present there are no antivirals or vaccines available fo DENV and there is no immune competent mouse model that recapitulates Dengue disease. DENV inhibits innate immune responses in infected cells by cleaving the adaptor molecule STING via the NS2B3 viral protease complex, which allows for the establishment of infection in those cells. With the experiments proposed in this application we aim to provide better models to study DENV and viral and host factors that can be used for drug design against DENV.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Cassetti, Cristina
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Manganaro, Lara; Pache, Lars; Herrmann, Tobias et al. (2014) Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF-?B-dependent manner. J Virol 88:7528-40
Opaluch, Amanda M; Schneider, Monika; Chiang, Chih-yuan et al. (2014) Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-?. PLoS One 9:e89284
Rajsbaum, Ricardo; Versteeg, Gijs A; Schmid, Sonja et al. (2014) Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKK? kinase-mediated antiviral response. Immunity 40:880-95
Brinzevich, Daria; Young, George R; Sebra, Robert et al. (2014) HIV-1 interacts with human endogenous retrovirus K (HML-2) envelopes derived from human primary lymphocytes. J Virol 88:6213-23
Morrison, Juliet; Laurent-Rolle, Maudry; Maestre, Ana M et al. (2013) Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling. PLoS Pathog 9:e1003265
Ramos, Irene; Krammer, Florian; Hai, Rong et al. (2013) H7N9 influenza viruses interact preferentially with *2,3-linked sialic acids and bind weakly to *2,6-linked sialic acids. J Gen Virol 94:2417-23
Suthar, Mehul S; Aguirre, Sebastian; Fernandez-Sesma, Ana (2013) Innate immune sensing of flaviviruses. PLoS Pathog 9:e1003541
Chiang, Chih-Yuan; Engel, Alex; Opaluch, Amanda M et al. (2012) Cofactors required for TLR7- and TLR9-dependent innate immune responses. Cell Host Microbe 11:306-18
Rodriguez-Madoz, Juan R; Belicha-Villanueva, Alan; Bernal-Rubio, Dabeiba et al. (2010) Inhibition of the type I interferon response in human dendritic cells by dengue virus infection requires a catalytically active NS2B3 complex. J Virol 84:9760-74
Rodriguez-Madoz, Juan R; Bernal-Rubio, Dabeiba; Kaminski, Dorota et al. (2010) Dengue virus inhibits the production of type I interferon in primary human dendritic cells. J Virol 84:4845-50

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