| Summary: | Rift Valley fever virus (RVFV) is a mosquito-borne virus that causes severe disease in people and livestock throughout Africa and the Arabian Peninsula. Human disease is usually self-limiting, but a small proportion of individuals develop fatal encephalitis. The role of the host immune response in determining disease outcome is largely unknown. In order to compare the quality and character of immune responses in nonfatal and fatal cases, we used an attenuated RVFV to inoculate mice by two routes. Subcutaneous inoculation resulted in a subclinical systemic infection that was rapidly cleared due to a robust adaptive response. In contrast, intranasal inoculation stimulated weaker immune responses that failed to control virus replication and culminated in uniformly fatal encephalitis. With many encephalitic viruses, the onset of disease is mediated by changes in blood brain barrier permeability and often, subsequent injury to the CNS by an uncontrolled immune response. However, our results suggest that development of RVFV disease does not depend on either mechanism, but rather results from direct virus-mediated damage in the CNS. Future therapeutic drug design should take into account all possible routes of virus exposure as well as the role of therapies that boost the adaptive response to better combat disease.
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