Abstract
Rift Valley fever virus (RVFV) is a major human and animal pathogen associated with severe disease including hemorrhagic fever or encephalitis. RVFV is endemic to parts of Africa and the Arabian Peninsula, but there is significant concern regarding its introduction into non-endemic regions and the potentially devastating effect to livestock populations with concurrent infections of humans. To date, there is little detailed data directly comparing the host response to infection with wild-type or vaccine strains of RVFV and correlation with viral pathogenesis. Here we characterized clinical and systemic immune responses to infection with wild-type strain ZH501 or IND vaccine strain MP-12 in the C57BL/6 mouse. Animals infected with live-attenuated MP-12 survived productive viral infection with little evidence of clinical disease and minimal cytokine response in evaluated tissues. In contrast, ZH501 infection was lethal, caused depletion of lymphocytes and platelets and elicited a strong, systemic cytokine response which correlated with high virus titers and significant tissue pathology. Lymphopenia and platelet depletion were indicators of disease onset with indications of lymphocyte recovery correlating with increases in G-CSF production. RVFV is hepatotropic and in these studies significant clinical and histological data supported these findings; however, significant evidence of a pro-inflammatory response in the liver was not apparent. Rather, viral infection resulted in a chemokine response indicating infiltration of immunoreactive cells, such as neutrophils, which was supported by histological data. In brains of ZH501 infected mice, a significant chemokine and pro-inflammatory cytokine response was evident, but with little pathology indicating meningoencephalitis. These data suggest that RVFV pathogenesis in mice is associated with a loss of liver function due to liver necrosis and hepatitis yet the long-term course of disease for those that might survive the initial hepatitis is neurologic in nature which is supported by observations of human disease and the BALB/c mouse model.
Highlights
Rift Valley fever virus (RVFV) is a highly pathogenic virus that can cause lethal disease in both humans and ruminant animals
RVF affects a broad range of animal species and is known to cause encephalitis or hemorrhagic fever in humans with survivors having long-term health effects such as a loss of vision
In this study we evaluated the host response to infection with either a RVFV vaccine strain or a wild-type strain to identify similarities or differences that could be exploited for development of therapeutics or improved vaccines
Summary
Rift Valley fever virus (RVFV) (family Bunyaviridae, genus Phlebovirus) is a highly pathogenic virus that can cause lethal disease in both humans and ruminant animals. RVFV is classified by the National Institute for Allergy and Infectious Diseases (NIAID) as a category A priority pathogen and is a United States Department of Agriculture (USDA) high priority pathogen. RVFV is historically endemic in sub-Saharan Africa, but recent outbreaks on the Arabian Peninsula have indicated an increased range for this virus. RVFV is transmitted primarily by Aedes mcintoshi mosquitoes, the virus has been detected in 23 species of mosquitoes [2]. Given the abundance of Aedes spp. in the United States and in other parts of the world, the potential introduction of RVFV into naıve populations is a very serious agricultural and public health concern [3,4]. Effective vaccines or therapeutic intervention are not commercially available for prevention or treatment of Rift Valley fever (RVF) in humans
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