In fatal Lassa fever (LF), an unchecked viremia leads to progressive signs and symptoms of hemorrhagic disease and shock. Since death occurs in the absence of extensive inflammation and tissue destruction, the fatal disease is most likely caused by virus-induced changes in host cell function, rather than by immunopathology. The molecular analysis of the virus-host cell interaction is therefore of great importance to understand the mechanisms of the disease and for the development of novel therapeutic strategies to treat critically ill patients. The interaction of a virus with its cellular receptors is a fundamental aspect of the virus-host cell relationship and a key determinant for the tissue tropism and the disease potential of a virus. Based on its pivotal importance for normal cell homeostasis and function, the cellular receptor of Lassa fever virus (LFV), alpha-dystroglycan (alpha-DG), is of particular interest regarding virus-induced cytopathology. In the host cell, atpha-DG provides an essential molecular link between the extracellular matrix (ECM) and the cytoskeleton. The glycoprotein (GP) of LFV binds alpha-DG with high affinity and efficiently competes with the interaction of alpha-DG with ECM proteins. Binding of LFVGP therefore likely interferes with the normal function of this important cellular receptor, contributing to virus-induced host cell dysfunction. Using a combination of biochemical and cell biological techniques, our study aims at the identification of alpha-DG-associated host cell proteins whose interactions, activation states, and cellular localization are changed by LFVGP binding. Since alpha-DG and its known binding partners are ubiquitously expressed cellular proteins, candidates identified by our study represent likely crucial targets of LFV critically involved in the pathogenesis of fatal LF. alpha-DG-associated proteins and signaling pathways that are affected by LFVGP will therefore be evaluated as potential targets for anti-viral therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065359-04
Application #
7632141
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$326,096
Indirect Cost
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Tsai, Wen-Yang; Youn, Han Ha; Tyson, Jasmine et al. (2018) Use of Urea Wash ELISA to Distinguish Zika and Dengue Virus Infections. Emerg Infect Dis 24:1355-1359
Thongsripong, Panpim; Chandler, James Angus; Green, Amy B et al. (2018) Mosquito vector-associated microbiota: Metabarcoding bacteria and eukaryotic symbionts across habitat types in Thailand endemic for dengue and other arthropod-borne diseases. Ecol Evol 8:1352-1368
Katzelnick, Leah C; Ben-Shachar, Rotem; Mercado, Juan Carlos et al. (2018) Dynamics and determinants of the force of infection of dengue virus from 1994 to 2015 in Managua, Nicaragua. Proc Natl Acad Sci U S A 115:10762-10767
Clemens, Daniel L; Lee, Bai-Yu; Horwitz, Marcus A (2018) The Francisella Type VI Secretion System. Front Cell Infect Microbiol 8:121
Huwyler, Camille; Heiniger, Nadja; Chomel, Bruno B et al. (2017) Dynamics of Co-Infection with Bartonella henselae Genotypes I and II in Naturally Infected Cats: Implications for Feline Vaccine Development. Microb Ecol 74:474-484
Norris, Michael H; Heacock-Kang, Yun; Zarzycki-Siek, Jan et al. (2017) Burkholderia pseudomallei natural competency and DNA catabolism: Identification and characterization of relevant genes from a constructed fosmid library. PLoS One 12:e0189018
Marques, Adriana R; Yang, Xiuli; Smith, Alexis A et al. (2017) Citrate Anticoagulant Improves the Sensitivity of Borreliella (Borrelia) burgdorferi Plasma Culture. J Clin Microbiol 55:3297-3299
Nualnoi, Teerapat; Norris, Michael H; Tuanyok, Apichai et al. (2017) Development of Immunoassays for Burkholderia pseudomallei Typical and Atypical Lipopolysaccharide Strain Typing. Am J Trop Med Hyg 96:358-367
Parameswaran, Poornima; Wang, Chunling; Trivedi, Surbhi Bharat et al. (2017) Intrahost Selection Pressures Drive Rapid Dengue Virus Microevolution in Acute Human Infections. Cell Host Microbe 22:400-410.e5
Bortell, Nikki; Flynn, Claudia; Conti, Bruno et al. (2017) Osteopontin Impacts West Nile virus Pathogenesis and Resistance by Regulating Inflammasome Components and Cell Death in the Central Nervous System at Early Time Points. Mediators Inflamm 2017:7582437

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