Aerosol exposure to Rift Valley fever virus causes earlier and more severe neuropathology in the murine model, which has important implications for therapeutic development

PLoS Negl Trop Dis. 2013 Apr 4;7(4):e2156. doi: 10.1371/journal.pntd.0002156. Print 2013.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiviral Agents
  • Disease Models, Animal
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Peripheral Nervous System Diseases / virology*
  • Ribavirin / therapeutic use
  • Rift Valley Fever / drug therapy*
  • Rift Valley Fever / immunology
  • Rift Valley Fever / pathology*
  • Rift Valley Fever / therapy*
  • Rift Valley fever virus / pathogenicity*
  • Viral Vaccines / therapeutic use

Substances

  • Antiviral Agents
  • Viral Vaccines
  • Ribavirin

Grants and funding

This work was supported by the Transformational Medical Technologies program from the Department of Defense Chemical and Biological Defense program through the Defense Threat Reduction Agency (Project No. TMT.DRUG.01.10.RD.002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.