Abstract
Currently there is no FDA-licensed vaccine or therapeutic against Sudan ebolavirus (SUDV) infections. The largest ever reported 2014–2016 West Africa outbreak, as well as the 2021 outbreak in the Democratic Republic of Congo, highlight the critical need for countermeasures against filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would greatly add to the screening of antivirals and vaccines. Here, we infected signal transducer and activator of transcription-1 knock out (STAT-1 KO) mice with five different wildtype filoviruses to determine susceptibility. SUDV and Marburg virus (MARV) were the most virulent, and caused 100% or 80% lethality, respectively. Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Taï Forest ebolavirus (TAFV) caused 40%, 20%, and no mortality, respectively. Further characterization of SUDV in STAT-1 KO mice demonstrated lethality down to 3.1 × 101 pfu. Viral genomic material was detectable in serum as early as 1 to 2 days post-challenge. The onset of viremia was closely followed by significant changes in total white blood cells and proportion of neutrophils and lymphocytes, as well as by an influx of neutrophils in the liver and spleen. Concomitant significant fluctuations in blood glucose, albumin, globulin, and alanine aminotransferase were also noted, altogether consistent with other models of filovirus infection. Finally, favipiravir treatment fully protected STAT-1 KO mice from lethal SUDV challenge, suggesting that this may be an appropriate small animal model to screen anti-SUDV countermeasures.
Highlights
The family Filoviridae includes Cuevavirus, Ebolavirus, and Marburgvirus, but only in the two latter genera can viruses pathogenic to humans be found [1,2,3]
A significant amount of work has been conducted in filovirus disease in a significant amount has been conducted in filovirus disease in small-rodent models [50], data of onwork the characterization of virulence and pathogenesis of small-rodent models
[50], data onEbola the characterization ofvirus virulence and pathogenesis ofmouse wild-type viruses other than virus or Marburg in immunocompromised wild-type viruses other thanYet, Ebola virus virus in immunocompromised models are still sparse. These dataor areMarburg critical for determining which relevant rodent mouseanimal modelsmodel are still sparse. These data are critical for determining relevant (s) may be used to achieve reproducible endpointswhich following infection, rodentinanimal model (s) may be used to achieve reproducible endpoints following order to get comparable virulence and pathogenesis data
Summary
The family Filoviridae includes Cuevavirus, Ebolavirus, and Marburgvirus, but only in the two latter genera can viruses pathogenic to humans be found [1,2,3]. In response to this, immunocompromised rodent models that lack one or more components of the immune response have been developed to study wild-type filovirus disease [19,28,29,30,31,32,33,34,35,36,37,38,39] and are used as platforms to evaluate anti-filovirus therapeutic and vaccine candidates [26,28,29,30,31,38,39,40,41,42,43,44,45,46,47] These models have included the interferon-α/β receptor knockout (IFNAR KO), the double interferon-α/β and γ receptor (IFNAGR) KO, interferon-γ receptor (IFNGR) KO, the cytoplasmic signal transducer and activator of transcription-1 protein (STAT-1) KO, the severe combined immunodeficiency (SCID) KO mice, and STAT-2 KO hamsters. As part of the NIH/NIAID Animal Models of Infectious Diseases Contract, we further characterized the virulence and pathogenicity of wild-type filoviruses in mice lacking the cytoplasmic signal transducer and activator of transcription-1 protein (STAT-1 KO)
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