Aerosol Exposure to Rift Valley Fever Virus Causes Earlier and More Severe Neuropathology in the Murine Model, which Has Important Implications for Therapeutic Development

Abstract

Rift Valley fever virus (RVFV) is an important mosquito-borne veterinary and human pathogen that can cause severe disease including acute-onset hepatitis, delayed-onset encephalitis, retinitis and blindness, or a hemorrhagic syndrome. Currently, no licensed vaccine or therapeutics exist to treat this potentially deadly disease. Detailed studies describing the pathogenesis of RVFV following aerosol exposure have not been completed and candidate therapeutics have not been evaluated following an aerosol exposure. These studies are important because while mosquito transmission is the primary means for human infection, it can also be transmitted by aerosol or through mucosal contact. Therefore, we directly compared the pathogenesis of RVFV following aerosol exposure to a subcutaneous (SC) exposure in the murine model by analyzing survival, clinical observations, blood chemistry, hematology, immunohistochemistry, and virus titration of tissues. Additionally, we evaluated the effectiveness of the nucleoside analog ribavirin administered prophylactically to treat mice exposed by aerosol and SC. The route of exposure did not significantly affect the survival, chemistry or hematology results of the mice. Acute hepatitis occurred despite the route of exposure. However, the development of neuropathology occurred much earlier and was more severe in mice exposed by aerosol compared to SC exposed mice. Mice treated with ribavirin and exposed SC were partially protected, whereas treated mice exposed by aerosol were not protected. Early and aggressive viral invasion of brain tissues following aerosol exposure likely played an important role in ribavirin's failure to prevent mortality among these animals. Our results highlight the need for more candidate antivirals to treat RVFV infection, especially in the case of a potential aerosol exposure. Additionally, our study provides an account of the key pathogenetic differences in RVF disease following two potential exposure routes and provides important insights into the development and evaluation of potential vaccines and therapeutics to treat RVFV infection.

Effects of Ribavirin on Severe Fever with Thrombocytopenia Syndrome Virus In Vitro

“…RVFV is another member of the Phlebovirus genus, for which both the in vitro and in vivo effects of ribavirin have been reported (22)(23)(24). Ribavirin reduced RVFV proliferation in a dose-dependent manner (Fig.…”

“…Peters et al reported that ribavirin at 23 mg/ml showed 2-log inhibition against RVFV in Vero cells (23). In animal models, ribavirin treatment (75-100 mg/kg/day) led to a 60z-75z survival rate in RVFV-inoculated mice (22)(23)(24), while it suppressed viremia in RVFV-infected monkeys (30 mg/kg/day, more than 2-log reduction of viral titers) (23). In the present study, the EC 99 of ribavirin in Vero cells against SFTSV .…”

Drivers of Rift Valley fever epidemics in Madagascar

“…However, most clinical cases occur after contact with blood, aborted fetuses, and placenta of viremic animals. Farmers, veterinarians, slaughterhouse workers, and butchers are thus the most exposed to the risk of RVF, as well as any people attending the slaughtering of viremic animals (11): Blood aerosol produced on this occasion is highly infectious (12). The virus is not transmitted from person to person.…”

High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection

“…23,24 However, in animal models, ribavirin has caused anemia and teratogenic effects, which has limited the application to compassionate use under investigational new drug protocols. 5,6 There are also other potential drugs in the development stage. 24,25 Therefore, there is a great need to find new drugs to treat human infection with better efficacy.…”

“…5 The efficacy in humans remains to be proven and there are undesirable side effects. 6 RVFV is an enveloped, negatively stranded RNA virus composed of three RNA segments, complexed with the nucleocapsid (N) protein.…”