Arenaviruses such as Lassa fever virus (LASV) can cause acute viral hemorrhagic fever disease in humans, to which there is no vaccine or effective treatment. Studies on basic biology, virulent mechanism, and pathogenesis of LASV are significantly hindered, partly due to the strict requirement for BSL-4 containment to work with this select agent and the lack of infectious clones. A small animal model for Lassa fever - guinea pig infected with a non-pathogenic Pichinde virus (PICV) within the same Arenaviridae family - has shown many similarities in the clinical and histopathological findings to lethal human Lassa fever infections. We have recently developed the infectious clones for two closely related PICV strains that show opposing disease outcomes in guinea pigs. In addition, we have developed safe and convenient systems to characterize arenavirus envelope glycoprotein (GPC)-mediated cell entry and LASV viral RNA synthesis in vitro. Based on our preliminary results, we hypothesize that the GPC-mediated cell entry and the polymerase protein L- dependent viral RNA synthesis represent two major virulence mechanisms of arenavirus. We propose to utilize the many molecular, genetic, and animal systems that are available in our laboratory to characterize the molecular determinants of virulent arenavirus infection in the infected hosts and to explore the virulence mechanisms of the GPC and L proteins at molecular level. Specifically, we wish to (1) characterize the molecular determinants for virulent infection in a guinea pig model of arenavirus hemorrhagic fever, (2) characterize the molecular mechanism of arenavirus GPC protein in cell entry pathways, (3) characterize the molecular mechanism of LASV L protein in viral RNA synthesis, viral replication, and virulence. These studies may lead to identification of potential therapeutic targets against Lassa fever and other arenavirus hemorrhagic fever diseases.

Public Health Relevance

Infection by Lassa fever virus or several other arenaviruses can lead to hemorrhagic fever (HF) diseases in humans, for which there is no vaccine (with the exception of Junin virus) or effective antiviral treatment. A related Pichinde virus in the same viral family is non-pathogenic in humans but causes distinct disease symptoms in guinea pigs that are similar to arenavirus HF in humans. We propose here to study the molecular mechanisms by which some arenaviruses can cause virulent infections in the hosts. These studies may lead to the development of effective treatments against the deadly arenavirus HF in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083409-05
Application #
8651859
Study Section
Virology - A Study Section (VIRA)
Program Officer
Repik, Patricia M
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$418,634
Indirect Cost
$143,217
Name
University of Minnesota Twin Cities
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
McLay, Lisa; Liang, Yuying; Ly, Hinh (2014) Comparative analysis of disease pathogenesis and molecular mechanisms of New World and Old World arenavirus infections. J Gen Virol 95:1-15
Wallat, Gregor D; Huang, Qinfeng; Wang, Wenjian et al. (2014) High-resolution structure of the N-terminal endonuclease domain of the Lassa virus L polymerase in complex with magnesium ions. PLoS One 9:e87577
Jiang, Xue; Huang, Qinfeng; Wang, Wenjian et al. (2013) Structures of arenaviral nucleoproteins with triphosphate dsRNA reveal a unique mechanism of immune suppression. J Biol Chem 288:16949-59
McLay, Lisa; Ansari, Aftab; Liang, Yuying et al. (2013) Targeting virulence mechanisms for the prevention and therapy of arenaviral hemorrhagic fever. Antiviral Res 97:81-92
McLay, Lisa; Lan, Shuiyun; Ansari, Aftab et al. (2013) Identification of virulence determinants within the L genomic segment of the pichinde arenavirus. J Virol 87:6635-43
Kumar, Naveen; Sharma, Nishi R; Ly, Hinh et al. (2011) Receptor tyrosine kinase inhibitors that block replication of influenza a and other viruses. Antimicrob Agents Chemother 55:5553-9
Kumar, Naveen; Liang, Yuhong; Parslow, Tristram G et al. (2011) Receptor tyrosine kinase inhibitors block multiple steps of influenza a virus replication. J Virol 85:2818-27
Qi, Xiaoxuan; Lan, Shuiyun; Wang, Wenjian et al. (2010) Cap binding and immune evasion revealed by Lassa nucleoprotein structure. Nature 468:779-83