Serum levels of inflammatory cytokines in Rift Valley fever patients are indicative of severe disease

Vuren, Petrus Jansen van; Shalekoff, Sharon; Grobbelaar, Antoinette A.; Archer, Brett N.; Thomas, Juno; Tiemessen, Caroline T.; Pawęska, Janusz T.

doi:10.1186/s12985-015-0392-3

Cited by 40 publications

(49 citation statements)

References 55 publications

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“…Serum samples from 26 patients from the 2000 outbreak of RVFV in Saudi Arabia showed increased WBC and decreased platelets in fatal cases relative to levels in survivors (6,41). Elevated CRE and urea levels were found in patient samples from lethal cases from the 2010 South African outbreak of RVFV (42). Granulocytosis has also been noted in NHPs exposed to aerosolized encephalitic alphaviruses, particularly in severe or fatal infections (43)(44)(45)(46), as well as in human Japanese encephalitis cases (47,48).…”

Section: Discussionmentioning

confidence: 98%

Peripheral Blood Biomarkers of Disease Outcome in a Monkey Model of Rift Valley Fever Encephalitis

Wonderlich

Caroline

McMillen

et al. 2018

J Virol

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Rift Valley Fever (RVF) is an emerging arboviral disease of livestock and humans. Although the disease is caused by a mosquito-borne virus, humans are infected through contact with, or inhalation of, virus-laden particles from contaminated animal carcasses. Some individuals infected with RVF virus (RVFV) develop meningoencephalitis, resulting in morbidity and mortality. Little is known about the pathogenic mechanisms that lead to neurologic sequelae, and thus, animal models that represent human disease are needed. African green monkeys (AGM) exposed to aerosols containing RVFV develop a reproducibly lethal neurological disease that resembles human illness. To understand the disease process and identify biomarkers of lethality, two groups of 5 AGM were infected by inhalation with either a lethal or a sublethal dose of RVFV. Divergence between lethal and sublethal infections occurred as early as 2 days postinfection (dpi), at which point CD8 T cells from lethally infected AGM expressed activated caspase-3 and simultaneously failed to increase levels of major histocompatibility complex (MHC) class II molecules, in contrast to surviving animals. At 4 dpi, lethally infected animals failed to demonstrate proliferation of total CD4 and CD8 T cells, in contrast to survivors. These marked changes in peripheral blood cells occur much earlier than more-established indicators of severe RVF disease, such as granulocytosis and fever. In addition, an early proinflammatory (gamma interferon [IFN-γ], interleukin 6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1]) and antiviral (IFN-α) response was seen in survivors, while very late cytokine expression was found in animals with lethal infections. By characterizing immunological markers of lethal disease, this study furthers our understanding of RVF pathogenesis and will allow the testing of therapeutics and vaccines in the AGM model. Rift Valley Fever (RVF) is an important emerging viral disease for which we lack both an effective human vaccine and treatment. Encephalitis and neurological disease resulting from RVF lead to death or significant long-term disability for infected people. African green monkeys (AGM) develop lethal neurological disease when infected with RVF virus by inhalation. Here we report the similarities in disease course between infected AGM and humans. For the first time, we examine the peripheral immune response during the course of infection in AGM and show that there are very early differences in the immune response between animals that survive infection and those that succumb. We conclude that AGM are a novel and suitable monkey model for studying the neuropathogenesis of RVF and for testing vaccines and therapeutics against this emerging viral pathogen.

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Section: Discussionmentioning

confidence: 98%

Peripheral Blood Biomarkers of Disease Outcome in a Monkey Model of Rift Valley Fever Encephalitis

Wonderlich

Caroline

McMillen

et al. 2018

J Virol

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“…Individuals who were infected with HIV had an increased mortality rate (75%) after RVFV infection compared to that of individuals who were HIV negative (28%), and all HIV-infected persons presented with CNS symptoms (24). In another study, 3 of 4 patients who presented with and succumbed to encephalitis were also found to be HIV positive (25). The known effects of HIV on the number and function of CD4 T cells suggest that individuals with T cell dysfunction might be at increased risk of developing severe RVFV disease, including encephalitis.…”

Section: Discussionmentioning

confidence: 96%

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

Harmon

Spengler

Coleman-McCray

et al. 2018

J Virol

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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.

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“…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. 28 The long-standing dogma holds that antibodies prevent viral disease, but T cells are needed to clear viral infection once the disease is manifest.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Rift Valley fever virus (RVFV) is a zoonotic arbovirus of clinical significance in both livestock and humans. A formalin-inactivated virus preparation was initially developed for human use and tested in laboratory workers in the 1960s. Vaccination resulted in generation of neutralizing antibody titers in most recipients, but neutralization titers waned over time, necessitating frequent booster doses. In this study, T cell-based immune responses to the formalin-inactivated vaccine were examined in a cohort of seven individuals who received between 1 and 6 doses of the vaccine. RVFV-specific T cell responses were detectable up to 24 years post vaccination. Peripheral blood mononuclear cells from this cohort of individuals were used to map out the viral epitopes targeted by T cells in humans. These data provide tools for assessing human RVFV-specific T cell responses and are thus a valuable resource for future human RVFV vaccine efforts.npj Vaccines (2020) 5:17 ; https://doi.

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Serum levels of inflammatory cytokines in Rift Valley fever patients are indicative of severe disease

Cited by 40 publications

References 55 publications

Peripheral Blood Biomarkers of Disease Outcome in a Monkey Model of Rift Valley Fever Encephalitis

Peripheral Blood Biomarkers of Disease Outcome in a Monkey Model of Rift Valley Fever Encephalitis

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

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

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