A Lethal Pseudofilovirus Model in Ifnar1(-/-) Mice Using Recombinant Vesicular Stomatitis Viruses
Anna V. Mamatkulova, Inna V. Shuliakova, Olga V. Zubkova, Dmitrii A. Reshetnikov, Anna A. Iliukhina, Ilya D. Zorkov, Daria M. Grousova, Daria M. Savina, Olga Popova, Denis I. Zrelkin, Polina P. Goldovskaya, Ekaterina G. Samokhvalova, Valentin V. Azizyan, Dmitry V. Shcheblyakov, Boris S. Naroditsky, Alexander L. Gintsburg, Denis Yu. LogunovFiloviruses cause highly lethal infectious diseases with hemorrhagic symptoms and extremely high fatality rate (up to 90%). Although two vaccines against Ebola virus (EBOV) are licensed for application in endemic areas, vaccines against other filoviruses (SUDV, BDBV, MARV) are still at pre-clinical or clinical stages. The development of vaccines requires protective efficacy studies using animal models of infection. However, animal studies using wild-type filoviruses require maximum biosafety level (BSL-4), which hinders filoviral vaccine advancement. In this study, we developed a surrogate animal model of EBOV-, SUDV-, BDBV- and MARV- GP-mediated entry using Ifnar1-knockout (-/-) mice and recombinant vesicular stomatitis viruses (rVSVs), carrying a genetic sequence of filoviral glycoprotein (GP) and pseudotyped with correspondent GP. We showed that rVSV-EBOV-GP was 100% lethal for Ifnar1(-/-) mice after inoculation by multiple routes, and its active propagation was within 24 h post-infection. We performed dose-dependent lethality assessment in small groups to estimate median lethal doses for rVSV-EBOV-GP, rVSV-SUDV-GP, rVSV-BDBV-GP, rVSV-MARV-GP in Ifnar1-knockout mice and showed high viral load in liver and immune cell reservoirs. The developed models contribute to safe and effective research of filoviral vaccines and therapeutic antibodies under BSL-2 conditions.