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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057159-09
Application #
8375451
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$441,561
Indirect Cost
$127,807
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
de Wispelaere, Mélissanne; Carocci, Margot; Liang, Yanke et al. (2017) Discovery of host-targeted covalent inhibitors of dengue virus. Antiviral Res 139:171-179
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
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
Vrentas, Catherine E; Moayeri, Mahtab; Keefer, Andrea B et al. (2016) A Diverse Set of Single-domain Antibodies (VHHs) against the Anthrax Toxin Lethal and Edema Factors Provides a Basis for Construction of a Bispecific Agent That Protects against Anthrax Infection. J Biol Chem 291:21596-21606
Helenius, Iiro Taneli; Nair, Aisha; Bittar, Humberto E Trejo et al. (2016) Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression. J Biomol Screen 21:363-71
Fink, Avner; Hassan, Musa A; Okan, Nihal A et al. (2016) Early Interactions of Murine Macrophages with Francisella tularensis Map to Mouse Chromosome 19. MBio 7:e02243

Showing the most recent 10 out of 412 publications