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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - A Study Section (VIRA)
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Repik, Patricia M
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University of Minnesota Twin Cities
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Dhanwani, Rekha; Ly, Hinh; Liang, Yuying (2017) Recombinant Tri-Segmented Pichinde Virus as a Novel Live Viral Vaccine Platform. Methods Mol Biol 1581:169-179
Shao, Junjie; Liu, Xiaoying; Ly, Hinh et al. (2016) Characterization of the Glycoprotein Stable Signal Peptide in Mediating Pichinde Virus Replication and Virulence. J Virol 90:10390-10397
Ly, Hinh; Liang, Yuying (2015) Immune evasion mechanisms of arenaviruses. Oncotarget 6:40386-7
Huang, Qinfeng; Shao, Junjie; Lan, Shuiyun et al. (2015) In vitro and in vivo characterizations of pichinde viral nucleoprotein exoribonuclease functions. J Virol 89:6595-607
Dhanwani, Rekha; Zhou, Yanqin; Huang, Qinfeng et al. (2015) A Novel Live Pichinde Virus-Based Vaccine Vector Induces Enhanced Humoral and Cellular Immunity after a Booster Dose. J Virol 90:2551-60
Xing, Junji; Ly, Hinh; Liang, Yuying (2015) The Z proteins of pathogenic but not nonpathogenic arenaviruses inhibit RIG-I-like receptor-dependent interferon production. J Virol 89:2944-55
Shao, Junjie; Liang, Yuying; Ly, Hinh (2015) Human hemorrhagic Fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis. Pathogens 4:283-306
Xing, Junji; Chai, Zheng; Ly, Hinh et al. (2015) Differential Inhibition of Macrophage Activation by Lymphocytic Choriomeningitis Virus and Pichinde Virus Is Mediated by the Z Protein N-Terminal Domain. J Virol 89:12513-7
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
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

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