CD4 T Cells, CD8 T Cells, and Monocytes Coordinate To Prevent Rift Valley Fever Virus Encephalitis

Abstract

Rift Valley fever virus (RVFV) is an arbovirus that causes disease in livestock and humans in Africa and the Middle East. While human disease is typically mild and self-limiting, some individuals develop severe manifestations, such as hepatitis, hemorrhagic fever, or encephalitis. Encephalitis occurs 2 to 3 weeks after acute illness; therefore, we hypothesized that it was a result of an inadequate adaptive immunity. To test this hypothesis in vivo, we used an attenuated virus (DelNSsRVFV) that does not typically cause disease in mice. We first characterized the normal immune response to infection with DelNSsRVFV in immunocompetent mice and noted expansion of natural killer cells and monocytes, as well as activation of both CD8 and CD4 T cells. Depleting C57BL/6 mice of CD4 T cells prior to DelNSsRVFV infection resulted in encephalitis in 30% of the mice; in encephalitic mice, we noted infiltration of T cells and inflammatory monocytes into the brain. CD4 and CD8 codepletion in C57BL/6 mice, as well as CD4 depletion in CCR2 knockout mice, increased the frequency of encephalitis, demonstrating that these cell types normally contributed to the prevention of disease. Encephalitic mice had similar viral RNA loads in the brain regardless of which cell types were depleted, suggesting that CD4 T cells, CD8 T cells, and inflammatory monocytes did little to control viral replication in the brain. CD4-depleted mice exhibited diminished humoral and T cell memory responses, suggesting that these immune mechanisms contributed to peripheral control of virus, thus preventing infection of the brain.IMPORTANCE RVFV is found in Africa and the Middle East and is transmitted by mosquitos or through contact with infected animals. Infected individuals can develop mild disease or more severe forms, such as hepatitis or encephalitis. In order to understand why some individuals develop encephalitis, we first need to know which immune functions protect those who do not develop this form of disease. In this study, we used a mouse model of RVFV infection to demonstrate that CD4 T cells, CD8 T cells, and monocytes all contribute to prevention of encephalitis. Their likely mechanism of action is preventing RVFV from ever reaching the brain.

Rift Valley fever virus vaccination induces long-lived, antigen-specific human T cell responses

“…A series of studies performed in the mouse model revealed that monocytes, CD4 T cells, and CD8 T cells played a role in preventing RVFV-mediated encephalitis in the context of an active innate immune response, and that B cells contributed to viral clearance. 12,13 These key findings suggested that T cells may be involved in modulating RVFV disease, and are further supported by the discovery that HIV- positive patients infected with RVFV had increased case fatality rates and increased occurrence of CNS manifestations of disease. 14,15 The role of antibodies in disease protection prior to or shortly following exposure to a pathogen is well-established in infectious disease.…”

“…Recent data obtained in the mouse model suggested that the T cellmediated immune response, not just the antibody response, could be important in protecting animals (and by extension, humans) from disease. 12,13 Additionally, two reports assessed HIV-positive patients who acquired RVFV infection; these patients exhibited increased frequency of central nervous system (CNS) symptoms and a significantly higher case fatality rate than HIV-negative patients, 14,15 suggesting the importance of CD4 T cells in preventing CNS manifestations and decreasing the severity of RVFV disease. Given these findings, it was of interest to quantitate and characterize T cell-mediated immune responses in humans.…”

Rift Valley Fever Virus Infection Causes Acute Encephalitis in the Ferret

“…Additionally, adaptive immunity could also modulate disease in humans since HIV-1-positive individuals are more likely to suffer from encephalitis (6,38). These phenomena are partially represented in murine models; mice with various forms of altered innate and/or adaptive immunity develop late-onset encephalitis following infection with a highly attenuated version of RVFV that has a deletion of the nonstructural small (NSs) protein, the major virulence factor (39,40). Additionally, BALB/c mice sometimes develop late-onset encephalitis (13) although the mechanisms that modulate this phenotype are unknown.…”

Natural killer cell responses to emerging viruses of zoonotic origin

“… Inhibition of type I IFN responses [ 167 , 168 , 169 ] Unclear . Reduced NK cell numbers in hyper-susceptible mice [ 170 ], but depletion does not increase susceptibility in resistant mice [ 171 ] Unlikely . NK cell depletion does not improve disease outcome in mice [ 171 ] Rabies Rhabdoviridae Bats, dogs, raccoons Bites Extremely rare Fever, nausea, vomiting.…”