Chemotactic and Inflammatory Responses in the Liver and Brain Are Associated with Pathogenesis of Rift Valley Fever Virus Infection in the Mouse

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.

Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus

“…We also found there was little to no change in IFN-c secretion after infection of C57BL/6 mice with either MP-12 or ZH501 (Gray et al, 2012). IFN-c was shown to play an important role during RVFV infection in rhesus macaques.…”

The Dominant-Negative Inhibition of Double-Stranded RNA-Dependent Protein Kinase PKR Increases the Efficacy of Rift Valley Fever Virus MP-12 Vaccine

“…The most susceptible target cells of wt RVFV in mice are hepatocytes (70), while the spleen removes blood-borne pathogens and cell debris from circulation (46). Replication of MP-12 is observed in mouse liver, although the titer is approximately 1,000 times lower than that of wt RVFV (20). Thus, it might be possible that MP-12 reaches the liver or spleen by escaping host immune responses at the draining lymph nodes, while rMP12-C13type or rMP12-mPKRN167 induces a local immune response in the draining lymph nodes.…”

Rift Valley Fever Virus MP-12 Vaccine Is Fully Attenuated by a Combination of Partial Attenuations in the S, M, and L Segments

“…Mice were therefore used as a model to evaluate MP-12 mutations. Even though mice are highly susceptible to RVFV infection, the pathology is not identical to that in human or ruminant RVFV infections, e.g., rapid neuroinvasion and a lack of febrile illness occur in mice but not commonly in humans and ruminants (9,74). In our model, major lesions could be detected in the liver and spleen at 3 and 4 dpi and in the brain at 5 dpi or later in mice infected with RVFV (Fig.…”