A Surrogate Animal Model for Screening of Ebola and Marburg Glycoprotein-Targeting Drugs Using Pseudotyped Vesicular Stomatitis Viruses.

Takeshi Saito,Wakako Furuyama,Ayato Takada,Hiroko Miyamoto,Kosuke Okuya,Shigeru Iida,Akina Mori-Kajihara,Yoshihiro Takadate,Takanari Hattori,Noriyo Nagata,Yurie Kida,Mao Isono,Shinya Ogawa,Junki Maruyama

doi:10.3390/v12090923

Abstract

Filoviruses, including Ebola virus (EBOV) and Marburg virus (MARV), cause severe hemorrhagic fever in humans and nonhuman primates with high mortality rates. There is no approved therapy against these deadly viruses. Antiviral drug development has been hampered by the requirement of a biosafety level (BSL)-4 facility to handle infectious EBOV and MARV because of their high pathogenicity to humans. In this study, we aimed to establish a surrogate animal model that can be used for anti-EBOV and -MARV drug screening under BSL-2 conditions by focusing on the replication-competent recombinant vesicular stomatitis virus (rVSV) pseudotyped with the envelope glycoprotein (GP) of EBOV (rVSV/EBOV) and MARV (rVSV/MARV), which has been investigated as vaccine candidates and thus widely used in BSL-2 laboratories. We first inoculated mice, rats, and hamsters intraperitoneally with rVSV/EBOV and found that only hamsters showed disease signs and succumbed within 4 days post-infection. Infection with rVSV/MARV also caused lethal infection in hamsters. Both rVSV/EBOV and rVSV/MARV were detected at high titers in multiple organs including the liver, spleen, kidney, and lungs of infected hamsters, indicating acute and systemic infection resulting in fatal outcomes. Therapeutic effects of passive immunization with an anti-EBOV neutralizing antibody were specifically observed in rVSV/EBOV-infected hamsters. Thus, this animal model is expected to be a useful tool to facilitate in vivo screening of anti-filovirus drugs targeting the GP molecule.

Highlights

The family Filoviridae includes five genera: Ebolavirus, Marburgvirus, Cuevavirus, Striavirus, and Thamnovirus
We evaluated replication-competent recombinant vesicular stomatitis viruses pseudotyped with Ebola virus (EBOV) and Marburg virus (MARV) GPs to determine their utility as surrogate viruses for in vivo drug screening under biosafety level (BSL)-2 conditions [27,28]
Using an enzyme-linked immunosorbent assay (ELISA), we detected high titers (>10,000) of EBOV GP-specific IgG antibodies in serum samples collected from the surviving animals, indicating that these animals were asymptomatically infected with the virus

Summary

Introduction

The family Filoviridae includes five genera: Ebolavirus, Marburgvirus, Cuevavirus, Striavirus, and Thamnovirus. The Ebolavirus genus contains five species—Zaire ebolavirus represented by Ebola virus (EBOV), Sudan ebolavirus, Taï Forest ebolavirus, Bundibugyo ebolavirus, and Reston ebolavirus. The Marburgvirus genus consists of only one species, Marburg marburgvirus including the prototype filovirus, Marburg virus (MARV) [1]. Except for Reston virus, members of genera Ebolavirus and Marburgvirus are known to cause severe hemorrhagic fever in humans and nonhuman primates (NHPs) with high mortality rates. The diseases caused by EBOV and MARV are known as Ebola virus disease (EVD) and Marburg virus disease (MVD), respectively [2,5,6]. EBOV and MARV infections of NHPs are the gold-standard models because they best represent similar pathogenesis of EVD or MVD in humans [3,11]. The use of NHPs in a high-biocontainment laboratory is associated with high cost and technical difficulties; some rodent models have been developed to deal with these problems [9,17,18,19,20]

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