Inflammatory Biomarkers Associated with Lethal Rift Valley Fever Encephalitis in the Lewis Rat Model

Caroline, Amy L.; Kujawa, Michael R.; Oury, Tim D.; Reed, Douglas S.; Hartman, Amy L.

doi:10.3389/fmicb.2015.01509

Cited by 20 publications

(51 citation statements)

References 40 publications

(62 reference statements)

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“…Although we have only a single time point at which to examine tissue-level cytokine production, this massive inflammatory response appears to be pathological. In longitudinal serial sacrifice experiments performed in rat and mouse models of RVFV encephalitis, high proinflammatory cytokines are found in the brain at end-stage disease but not earlier (20,50).…”

Section: Discussionmentioning

confidence: 98%

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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%

“…Tissue specimens obtained at necropsy were first homogenized in cell culture medium and then used for virus titration. Virus was measured in biological samples using a standard viral plaque assay and TaqMan q-RT-PCR as described previously (20).…”

Section: Ethicsmentioning

confidence: 99%

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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“…Rats develop severe disease after RVFV infection, similar to that observed in domesticated livestock and humans (21, 22). We have previously used rats to study different disease outcomes resulting from RVFV infection (21, 23). Although there are significant morphologic differences between the placentas of humans and rodents, rats are often used to study placental development, embryogenesis, embryotoxicity, and vaccine teratogenicity during pregnancy (24-29).…”

Section: Resultsmentioning

confidence: 99%

Rift Valley fever virus induces fetal demise through direct placental infection

Arora

et al. 2018

Preprint

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14Rift Valley fever virus (RVFV) infections in pregnant livestock are associated with high 15 rates of fetal demise and have been linked to miscarriage in pregnant women. To address how 16 acute RVFV infection during pregnancy causes detrimental effects on the fetus, we developed an 17 immunocompetent pregnant rodent model of RVFV infection. We found that pregnant rats were 18 more susceptible to RVFV-induced death than their non-pregnant counterparts and that RVFV 19 infection resulted in intrauterine fetal death and severe congenital abnormalities, even in pups from 20 infected asymptomatic pregnant rats. Virus distribution in infected dams was widespread, with a 21 previously unrecognized preference for infection, replication, and tissue damage in the placenta. 22In human mid-gestation placental tissue, RVFV directly infected placental chorionic villi, with 23 replication detected in the outermost syncytial layer. Our work identifies direct placental infection 24 by RVFV as a mechanism for vertical transmission and points to the teratogenic potential of this 25 virus in humans. This is the first time vertical transmission of RVFV has been shown in species 26

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“…Weakened in ammatory responses from RVFV infection has been suggested to contribute to RVFV pathogenesis and fatality (Nfon et al, 2012). Contrary to these suggestions, a recent body of evidence (Caroline et al, 2016;van Vuren et al, 2015;Gray et al, 2012) suggests that deregulation and prolonged in ammation correlate with viral pathogenesis and fatality. The combination of this contradicting in ammatory evidence and the IFNs inhibitory role of the NSs led to the hypothesis that unbalanced and deregulated in ammation could be central to the RVFV pathogenesis and lethality.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Lithium on Inflammation Profiles and Nf-κB Nuclear Translocation in Raw 264.7 Macrophages Exposed to Rift Valley Fever Virus

Makola¹,

Kgaladi²,

More³

et al. 2020

Preprint

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IntroductionRift Valley fever virus is a mosquito-transmitted zoonotic viral infection that results in Rift Valley fever disease. RVFV and other viruses have developed mechanism to circumvent the immune recognition in an attempt to advance their viral progeny. The RVFV S segment encodes a non-structural protein (NSs) known to be the main virulence factor that aid in immune suppression and viral replication. Thus, this study is aimed at investigating the inflammatory effects of lithium using macrophages as innate immune model.MethodsThe supernatant from RVFV-infected Raw 264.7 cells and treated with lithium, was examined with Elisa assay kit to measure production levels of the cytokines and chemokines. The H2DCF-DA and DAF-2 DA oxidant florigenic assays were used to determine the levels of ROS and RNS by measuring the fluorescence intensity shown by the cells post RVFV-infection and lithium treatment. While on the other hand Western blotting assay was used to measure expression levels of the inflammatory proteins and immunocytochemistry measured the cellular location of the NF-κB.ResultsLithium have shown to stimulate production of IFN-γ 3 hrs pi and reached its peak 12 hrs later. Moreover, the secondary pro-inflammatory cytokine and chemokine, IL-6, and RANTES were elevated at 12 hrs pi. Lithium was shown to stimulate expression of the primary pro-inflammatory molecule, TNF-α as early as 3 hrs pi. In addition to TNF-α expression, the regulatory cytokine, IL-10, was stimulated by lithium and reached its peak 12 hrs pi. The RVFV-infected cells treated with lithium have shown lowered ROS and RNS production as opposed to lithium-free RVFV-infected control cells. The regulatory properties of lithium were further supported by the protein expression assay that showed low expression of the iNOS while stimulating heme oxygenase (HO) and IκB. Lithium was shown to reverse NF-κB nuclear translocation in RVFV-infected Raw 264.7 cells as shown by the Immunocytochemistry assay. Moreover, lithium lowered the presence of nuclear NF-κB in RVFV-infected cells as opposed to untreated RVFV-infected cells and 5 mg/ml LPS controls as shown by the protein expression assay.ConclusionThis study demonstrates that lithium inhibits NF-kB nuclear translocation and modulate inflammation profiles in RVFV-infected Raw 264.7 cells.

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Inflammatory Biomarkers Associated with Lethal Rift Valley Fever Encephalitis in the Lewis Rat Model

Cited by 20 publications

References 40 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

Rift Valley fever virus induces fetal demise through direct placental infection

The Effects of Lithium on Inflammation Profiles and Nf-κB Nuclear Translocation in Raw 264.7 Macrophages Exposed to Rift Valley Fever Virus

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