Rift valley Fever virus encephalitis is associated with an ineffective systemic immune response and activated T cell infiltration into the CNS in an immunocompetent mouse model.

Kimberly A Dodd,Anita K Mcelroy,Tara L Jones,Stuart T Nichol,Sherif R Zaki,Christina F Spiropoulou,Remi Charrel

doi:10.1371/journal.pntd.0002874

Abstract

BackgroundRift Valley fever virus (RVFV) causes outbreaks of severe disease in livestock and humans throughout Africa and the Arabian Peninsula. In people, RVFV generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. One manifestation is a delayed-onset encephalitis that can be fatal or leave the afflicted with long-term neurologic sequelae. In order to design targeted interventions, the basic pathogenesis of RVFV encephalitis must be better understood.Methodology/Principal FindingsTo characterize the host immune responses and viral kinetics associated with fatal and nonfatal infections, mice were infected with an attenuated RVFV lacking NSs (ΔNSs) that causes lethal disease only when administered intranasally (IN). Following IN infection, C57BL/6 mice developed severe neurologic disease and succumbed 7–9 days post-infection. In contrast, inoculation of ΔNSs virus subcutaneously in the footpad (FP) resulted in a subclinical infection characterized by a robust immune response with rapid antibody production and strong T cell responses. IN-inoculated mice had delayed antibody responses and failed to clear virus from the periphery. Severe neurological signs and obtundation characterized end stage-disease in IN-inoculated mice, and within the CNS, the development of peak virus RNA loads coincided with strong proinflammatory responses and infiltration of activated T cells. Interestingly, depletion of T cells did not significantly alter survival, suggesting that neurologic disease is not a by-product of an aberrant immune response.Conclusions/SignificanceComparison of fatal (IN-inoculated) and nonfatal (FP-inoculated) ΔNSs RVFV infections in the mouse model highlighted the role of the host immune response in controlling viral replication and therefore determining clinical outcome. There was no evidence to suggest that neurologic disease is immune-mediated in RVFV infection. These results provide important insights for the future design of vaccines and therapeutic options.

Highlights

Rift Valley fever virus (RVFV) is a zoonotic arbovirus that has serious public health, veterinary and economic impacts throughout Africa and the Arabian Peninsula
The results indicated that severe neurologic disease developed following a reduced systemic immune response, and raised the question of whether neurologic disease resulted from direct viral damage to the CNS or to pathology resulting from disruption of the blood brain barrier and an unregulated immune response
Encephalitis is a serious and occasionally fatal complication of human RVFV infection, little is known about the factors contributing to this disease outcome

Summary

Introduction

Rift Valley fever virus (RVFV) is a zoonotic arbovirus that has serious public health, veterinary and economic impacts throughout Africa and the Arabian Peninsula. RVFV infection is generally described as a self-limiting febrile illness marked by severe arthralgia, myalgia, photophobia and headache. Most individuals recover without long-term sequelae, some human infections progress to a serious hepatitis, hemorrhagic syndrome or delayed onset encephalitis. In these most severely afflicted patients, case fatality can be greater than 20% [1,2], and survivors of the encephalitic syndrome frequently suffer from long-term neurological complications. Rift Valley fever virus (RVFV) causes outbreaks of severe disease in livestock and humans throughout Africa and the Arabian Peninsula. RVFV generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. In order to design targeted interventions, the basic pathogenesis of RVFV encephalitis must be better understood

Methods

Results

Conclusion