Abstract
Several arenaviruses are highly pathogenic to humans, causing hemorrhagic fever. Discovery of anti-arenavirus drug candidates is urgently needed, although the molecular basis of the host- and organ-specific pathogenicity remains to be fully elucidated. The arenavirus Z protein facilitates production of virus-like particles (VLPs), providing an established method to assess virus budding. In this study, we examined the efficiency of VLP production by solely expressing Z protein of several different arenaviruses. In addition, we analyzed the role of the late (L)-domain of the arenavirus Z protein, which is essential for the interaction with ESCRT proteins, in VLP production among different cell lines. VLP assay was performed using Z proteins of Junín virus (JUNV), Machupo virus (MACV), Tacaribe virus (TCRV), Latino virus (LATV), Pichinde virus (PICV), and Lassa virus (LASV) in six different cell lines: HEK293T, Huh-7, A549, Vero76, BHK-21, and NIH3T3 cells. JUNV, MACV, and LASV Z proteins efficiently produced VLPs in all tested cell lines, while the efficiencies of VLP production by the other arenavirus Z proteins were cell type-dependent. The contribution of the L-domain(s) within Z protein to VLP production also highly depended on the cell type. These results suggested that each arenavirus has its own particle-production mechanism, which is different among the cell types.
Highlights
Several arenaviruses including Lassa, Lujo, Junín, Machupo, Guanarito, Sabia, and Chapare viruses (LASV, LUJV, Junín virus (JUNV), Machupo virus (MACV), GTOV, SABV, and CHPV) cause severe symptoms such as hemorrhagic fever
Virus-Like Particle (VLP) production in Latino virus (LATV) Z A549 and BHK-21 cells was significantly lower relative to JUNV Z (25% and 11%, respectively). These data show that the efficiency of Z-mediated VLP production of Tacaribe virus (TCRV), Pichinde virus (PICV), and LATV is cell-type dependent
VLP production was completely abolished in NIH3T3 cells expressing the Mut protein (Figure 4F). These results clearly indicate that the PTAP motif plays a critical role in JUNV Z-mediated VLP production, and the degree of importance of the L-domain is dependent on cell type. (ii) Role of the PSAP Motif in MACV Z-Mediated VLP Production MACV Z contains a PSAP motif in its C-terminus (Figure 2B) (Urata and de la Torre, 2011; Urata and Yasuda, 2012)
Summary
Several arenaviruses including Lassa, Lujo, Junín, Machupo, Guanarito, Sabia, and Chapare viruses (LASV, LUJV, JUNV, MACV, GTOV, SABV, and CHPV) cause severe symptoms such as hemorrhagic fever. There is currently no vaccine or drug approved by the Food and Drug Administration (FDA) (Buchmeier et al, 2007). L-Domain Utilities of Arenaviruses contacts with body fluids of infected humans or animals, bites by infected rodents, or aerosol inhalation of their excretions. Arenaviruses are classified into two groups: Old World (OW) arenaviruses including LASV and LUJV; and New World (NW) arenaviruses including JUNV, MACV, GTOV, SABV, and CHPV (Charrel et al, 2008). Distribution of arenaviruses is closely related to that of the natural reservoir, rodents. Due to an increase in international travel over the past few decades, a potential risk for the worldwide spread of arenavirus has attracted a lot of attention from public health organizations (McCormick et al, 1986; Ericsson et al, 2001)
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