Abstract
Rift Valley fever virus (RVFV) is a zoonotic arbovirus affecting humans and livestock in Africa and the Arabian Peninsula. The majority of human cases are mild and self-limiting; however, severe cases can result in hepatitis, encephalitis, or hemorrhagic fever. There is a lack of immunocompetent mouse models that faithfully recapitulate the varied clinical outcomes of RVF in humans. However, there are easily accessible and commonly used inbred mouse strains that have never been challenged with wild-type RVFV. Here, RVFV susceptibility and pathogenesis were evaluated across five commonly used inbred laboratory mouse strains: C57BL/6J, 129S1/SvlmJ, NOD/ShiLtJ, A/J, and NZO/HILtJ. Comparisons between different mouse strains, challenge doses, and sexes revealed exquisite susceptibility to wild-type RVFV in an almost uniform manner. Never before challenged NOD/ShiLtJ, A/J, and NZO/HILtJ mice showed similar phenotypes of Rift Valley fever disease as previously tested inbred mouse strains. The majority of infected mice died or were euthanized by day 5 post-infection due to overwhelming hepatic disease as evidenced by gross liver pathology and high viral RNA loads in the liver. Mice surviving past day 6 across all strains succumbed to late-onset encephalitis. Remarkably, sex was not found to impact survival or viral load and showed only modest effect on time to death and weight loss for any of the challenged mouse strains following RVFV infection. Regardless of sex, these inbred mouse strains displayed extreme susceptibility to wild-type RVFV down to one virus particle.
Highlights
Rift Valley fever (RVF) is a disease of humans and livestock causing severe economic and human health impacts (Hartman, 2017)
The vast majority of human RVF virus (RVFV) infections result in self-limited febrile illnesses, but 10–20% of identified human cases progress to severe hepatitis, hemorrhagic fever, or encephalitis (Laughlin et al, 1978; Strausbaugh et al, 1978; Nanyingi et al, 2015)
As would be expected given the probability of delivering a live virus particle to each mouse when administering such a small dose, most of these “survivor” mice at this 0.2 tissue culture infective dose 50 (TCID50) challenge dose were confirmed to be uninfected by a negative terminal serum ELISA result and negative Quantitative RT-PCR (qRT-PCR) of liver, spleen, brain, and testes tissues (Figure 1B)
Summary
Rift Valley fever (RVF) is a disease of humans and livestock causing severe economic and human health impacts (Hartman, 2017). RVF spans a variety of clinical manifestations, ranging from an acute flu-like illness to a more severe and sometimes lethal form of disease (Laughlin et al, 1979). The vast majority of human RVF virus (RVFV) infections result in self-limited febrile illnesses, but 10–20% of identified human cases progress to severe hepatitis, hemorrhagic fever, or encephalitis (Laughlin et al, 1978; Strausbaugh et al, 1978; Nanyingi et al, 2015). These large variations in human RVF disease progression and outcome are inadequately represented in the current small animal models. This lack of accurate recapitulation of human disease continues to limit our understanding of RVFV pathogenesis
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