Overexpression of Tumor Necrosis Factor Alpha by a Recombinant Rabies Virus Attenuates Replication in Neurons and Prevents Lethal Infection in Mice

Faber, Milosz; Bette, Michael; Preuss, Mirjam A. R.; Pulmanausahakul, Rojjanaporn; Rehnelt, Jennifer; Schnell, Matthias J.; Dietzschold, Bernhard; Weihe, Eberhard

doi:10.1128/jvi.79.24.15405-15416.2005

Cited by 47 publications

(33 citation statements)

References 42 publications

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“…Schijns and colleagues [28] reported that vaccine induced antibody responses against inactivated rabies antigen can be increased by administering cytokines like TNFalpha, IL-1, IL-2 and IFN-gamma and thus, improves the vaccine efficacy. Besides, Faber and colleagues showed that TNF-alpha exhibits antiviral activity against rabies virus infection by inducing inflammatory response [29]. In our study also, we report that the extract 300ET enhanced inflammatory cytokine production like TNF-alpha and IL-1 beta that could possibly aid in viral clearance.…”

Section: Resultssupporting

confidence: 65%

Supercritical Carbon Dioxide Extract of Seabuckthorn Leaves Enhances Rabies Virus Neutralizing Antibody Titers and CTL Response in Swiss Albino Mice

Jayashankar¹,

Singh²,

Mishra³

et al. 2016

J Vaccines Immunol

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Introduction: Rabies is a viral disease that causes nearly thousands of death globally per year. Vaccination against rabies generates virus neutralizing antibodies and is the most successful and cost effective method of preventing the disease. In the present study, we have evaluated the adjuvant property of supercritical carbon dioxide extract (SCE) 300ET of Seabuckthorn (SBT) leaves against inactivated rabies virus antigen in Swiss albino mice. Methods:Mice were grouped as PBS control; inactivated rabies antigen (Rb) control; 300ET+Rb and Algel+Rb. All the mice were primed on day 1 followed by single booster at day 14. Sera were collected at different time points for RVNA analysis. Additionally, the effect of SCE on CD8 + Granzyme B + Cytotoxic T Lymphocyte (CTL) response, surface markers and cytokine levels were measured. Result:The results showed enhanced rabies virus neutralizing antibody (RVNA) titres using 300ET as compared to control and Algel groups as measured by Rapid Fluorescent Focus Inhibition Test (RFFIT). Moreover, the extract 300ET and Algel showed increased CD138 + (plasma cells) and CD11c + (dendritic cells) cell population as compared to the inactivated rabies antigen immunized mice. The extract 300ET also stimulated cellular immunity by showing heightened CTL response and proinflammatory cytokines level such as TNF-α and IL-1β. Conclusion:Hence, our results suggested that SCE300ET exhibits adjuvant activity by effectively enhancing antibody as well as cell mediated immunity in response to inactivated rabies antigen. Thus, SCE could be considered as a potential adjuvant candidate for rabies vaccines.

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Section: Resultssupporting

confidence: 65%

Supercritical Carbon Dioxide Extract of Seabuckthorn Leaves Enhances Rabies Virus Neutralizing Antibody Titers and CTL Response in Swiss Albino Mice

Jayashankar¹,

Singh²,

Mishra³

et al. 2016

J Vaccines Immunol

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“…This was confirmed in ZF4 cells because stimulation of these cells with TNF-␣ resulted in an increased number of plaques and their area even though it moderately triggers the expression of Mx in these cells. In sharp contrast, using recombinant rabies virus engineered to express either soluble or membrane-bound TNF-␣, it has recently been shown that brains of mice infected intranasally with virus expressing soluble TNF-␣ show significantly less virus dissemination than mouse brains from a mock infection (52). In addition, none of the soluble TNF-␣-infected mice succumbed to rabies virus infection, whereas 80% of mock-infected mice died.…”

Section: Discussionmentioning

confidence: 94%

“…In addition, none of the soluble TNF-␣-infected mice succumbed to rabies virus infection, whereas 80% of mock-infected mice died. Interestingly, however, the expression of either form of TNF-␣ was not associated with increased cell death or induction of ␣/␤ IFNs in a cell line (52). Furthermore, reduced virus spread in soluble TNF-␣ recombinant virus-infected mouse brains was matched by enhanced CNS inflammation, including T cell infiltration and microglial activation, suggesting that TNF-␣ exerts its protective activity in the brain directly through an IFN-independent, as yet unknown, antiviral mechanism and indirectly through the induction of inflammatory processes in the CNS.…”

Section: Discussionmentioning

confidence: 99%

Evolution of the Inflammatory Response in Vertebrates: Fish TNF-α Is a Powerful Activator of Endothelial Cells but Hardly Activates Phagocytes

Roca

Mulero

López-Muñoz

et al. 2008

The Journal of Immunology

180

106

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TNF-α is conserved in all vertebrate classes and has been identified in all taxonomic groups of teleost fish. However, its biological activities and its role in infection are largely unknown. Using two complementary fish models, gilthead seabream and zebrafish, we report here that the main proinflammatory effects of fish TNF-α are mediated through the activation of endothelial cells. Thus, TNF-α promotes the expression of E-selectin and different CC and CXC chemokines in endothelial cells, thus explaining the recruitment and activation of phagocytes observed in vivo in both species. We also found that TLR ligands, and to some extent TNF-α, were able to increase the expression of MHC class II and CD83 in endothelial cells, which might suggest a role for fish endothelial cells and TNF-α in Ag presentation. Lastly, we found that TNF-α increases the susceptibility of the zebrafish to viral (spring viremia of carp virus) and bacterial (Streptococcus iniae) infections. Although the powerful actions of fish TNF-α on endothelial cells suggest that it might facilitate pathogen dissemination, it was found that TNF-α increased antiviral genes and, more importantly, had little effect on the viral load in early infection. In addition, the stimulation of ZF4 cells with TNF-α resulted in increased viral replication. Together, these results indicate that fish TNF-α displays different sorts of bioactivity to their mammalian counterparts and point to the complexity of the evolution that has taken place in the regulation of innate immunity by cytokines.

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“…The recombinant RABVs SPBN(Ϫ) and SPBN␥ were engineered as described previously (33). For SPBN␥, murine IFN-␥ DNA was PCR amplified from mRNA extracted from RABV-infected mouse brain tissue using the custom primers (IDT, Coralville, IA) described below and DeepVent polymerase (NEB, Ipswich, MA).…”

Section: Methodsmentioning

confidence: 99%

Expression of Interferon Gamma by a Recombinant Rabies Virus Strongly Attenuates the Pathogenicity of the Virus via Induction of Type I Interferon

Barkhouse

Garcia

Bongiorno

et al. 2015

J Virol

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Previous animal model experiments have shown a correlation between interferon gamma (IFN-␥) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-␥ by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-␥ gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBN␥. Morbidity and mortality were monitored in mice infected intranasally with SPBN␥ or SPBN(؊) control virus to determine the degree of attenuation caused by the expression of IFN-␥. Incorporation of IFN-␥ into the rabies virus genome highly attenuated the virus. SPBN␥ has a 50% lethal dose (LD 50) more than 100-fold greater than SPBN(؊). In vitro and in vivo mouse experiments show that SPBN␥ infection enhances the production of type I interferons. Furthermore, knockout mice lacking the ability to signal through the type I interferon receptor (IFNAR ؊/؊ ) cannot control the SPBN␥ infection and rapidly die. These data suggest that IFN-␥ production has antiviral effects in rabies, largely due to the induction of type I interferons. IMPORTANCE Survival from rabies is dependent upon the early control of virus replication and spread. Once the virus reaches the central nervous system (CNS), this becomes highly problematic. Studies of CNS immunity to RABV have shown that control of replication begins at the onset of T cell entry and IFN-␥ production in the CNS prior to the appearance of virus-neutralizing antibodies.Moreover, antibody-deficient mice are able to control but not clear attenuated RABV from the CNS. We find here that IFN-␥ triggers the early production of type I interferons with the expected antiviral effects. We also show that engineering a lethal rabies virus to express IFN-␥ directly in the infected tissue reduces rabies virus replication and spread, limiting its pathogenicity in normal and immunocompromised mice. Therefore, vector delivery of IFN-␥ to the brain may have the potential to treat individuals who would otherwise succumb to infection with rabies virus. R abies virus (RABV) is the type species of the Lyssavirus genus in the Rhabdoviridae family. Its small, negative-stranded RNA genome contains only five true genes (1, 2). Although relatively simple, this zoonotic virus has a devastating impact worldwide. The majority of human rabies deaths occur in children in the developing world, and it is estimated that at least 55,000 humans die of rabies each year in Africa and Asia alone (3).Although RABV infection historically has been viewed as a death sentence once the virus reaches the brain, there is a small but growing number of humans who have survived rabies even though the virus entered the brain (4, 5). Due to such cases and to research using animal models of RABV infection (6-8), many believe that the immune system may be cap...

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Overexpression of Tumor Necrosis Factor Alpha by a Recombinant Rabies Virus Attenuates Replication in Neurons and Prevents Lethal Infection in Mice

Abstract: The effect of tumor necrosis factor alpha (TNF-␣) on rabies virus (RV) infection

Cited by 47 publications

References 42 publications

Supercritical Carbon Dioxide Extract of Seabuckthorn Leaves Enhances Rabies Virus Neutralizing Antibody Titers and CTL Response in Swiss Albino Mice

Supercritical Carbon Dioxide Extract of Seabuckthorn Leaves Enhances Rabies Virus Neutralizing Antibody Titers and CTL Response in Swiss Albino Mice

Evolution of the Inflammatory Response in Vertebrates: Fish TNF-α Is a Powerful Activator of Endothelial Cells but Hardly Activates Phagocytes

Expression of Interferon Gamma by a Recombinant Rabies Virus Strongly Attenuates the Pathogenicity of the Virus via Induction of Type I Interferon

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