NERCE Project 17: Innate immunity hemorrhagic fever viruses, Robert W. Finberg, M.D., UMass The innate immune response to hemorrhagic fever viruses determines the early morbidity and mortality associated with these illnesses. This is a consequence of both induction of host inflammatory cytokines by the virus, as well as the initial host defense against the virus which includes the production of type 1 interferons (IFN) that prevent viruses from replicating. Our initial series of experiments defined the Toll Like Receptor (TLR) responses to hemorrhagic fever viruses, focusing on Lymphocytic Choriomeningitis Virus (LCMV) as a prototypic arenavirus. By using human cells transfected with CD14 and TLR2 and knockout mice, we were able to demonstrate that the LCMV specific inflammatory cytokine response is mediated through TLR2, TLR6, and CD14. Screening for small molecules that inhibited LCMV-mediated activation of NFkB, defined a subset of compounds that may be suitable for preventing TLR2 mediated viral disease by blocking the induction of inflammatory cytokines (""""""""cytokine storm"""""""") associated with many lethal viral infections. Our studies of the responses of mouse and human cells to the arenavirus LCMV, and two filoviruses that cause hemorrhagic fever, namely Ebola and Marburg, reveal that these viruses cause a rapid induction of inflammatory cytokines in host cells. We plan to use the compounds we have identified as a result of our screen, in human cells and in mouse models challenged with different hemorrhagic fever to define the mechanisms of action of these small molecules and determine if they can prevent the """"""""cytokine storm"""""""". Initial virus containment in mammals is dependent upon the induction of type 1 IFN, which is commonly mediated through cytoplasmic RNA helicases termed RIG-l-like receptors. In this project we will define the genes and pathways involved in the induction of IFN by hemorrhagic fever viruses and search for small molecules that might augment that response. In addition we will investigate host genes directly or indirectly modulated by infection with these viruses and the effects of the small molecules obtained through our screens on expression of these genes

Public Health Relevance

These studies will define how viruses that cause hemorrhagic fevers interact with the host innate immune system. Small molecules that affect this interaction will be identified. Together, these studies will lead to new approaches to treating and preventing diseases caused by these viruses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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Harvard University
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de Wispelaere, Melissanne; Lian, Wenlong; Potisopon, Supanee et al. (2018) Inhibition of Flaviviruses by Targeting a Conserved Pocket on the Viral Envelope Protein. Cell Chem Biol 25:1006-1016.e8
Huang, Nai-Jia; Pishesha, Novalia; Mukherjee, Jean et al. (2017) Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin. Nat Commun 8:423
Mertins, Philipp; Przybylski, Dariusz; Yosef, Nir et al. (2017) An Integrative Framework Reveals Signaling-to-Transcription Events in Toll-like Receptor Signaling. Cell Rep 19:2853-2866
Nair, Dhanalakshmi R; Chen, Ji; Monteiro, João M et al. (2017) A quinolinol-based small molecule with anti-MRSA activity that targets bacterial membrane and promotes fermentative metabolism. J Antibiot (Tokyo) 70:1009-1019
Choo, Min-Kyung; Sano, Yasuyo; Kim, Changhoon et al. (2017) TLR sensing of bacterial spore-associated RNA triggers host immune responses with detrimental effects. J Exp Med 214:1297-1311
de Wispelaere, Mélissanne; Carocci, Margot; Liang, Yanke et al. (2017) Discovery of host-targeted covalent inhibitors of dengue virus. Antiviral Res 139:171-179
Umetsu, Dale T (2017) Mechanisms by which obesity impacts upon asthma. Thorax 72:174-177
Zheng, Huiqing; Colvin, Christopher J; Johnson, Benjamin K et al. (2017) Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence. Nat Chem Biol 13:218-225
Coulson, Garry B; Johnson, Benjamin K; Zheng, Huiqing et al. (2017) Targeting Mycobacterium tuberculosis Sensitivity to Thiol Stress at Acidic pH Kills the Bacterium and Potentiates Antibiotics. Cell Chem Biol 24:993-1004.e4
Carocci, Margot; Yang, Priscilla L (2016) Lactimidomycin is a broad-spectrum inhibitor of dengue and other RNA viruses. Antiviral Res 128:57-62

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