Infection of monocytes or immature dendritic cells (DCs) with an attenuated rabies virus results in DC maturation and a strong activation of the NFκB signaling pathway

Li, Jianwei; McGettigan, James P.; Faber, Milosz; Schnell, Matthias J.; Dietzschold, Bernhard

doi:10.1016/j.vaccine.2007.10.072

Cited by 41 publications

(54 citation statements)

References 26 publications

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“…The recombinant RV vaccine SPBNGAS is based on the prototype recombinant virus SPBN, which was derived from the SAD B19 cDNA clone (17). The generation of the double G variant of SPBN is described elsewhere (12,13). All RV vaccine strains were propagated in BSR (a BHK-21 clone) (18) cells.…”

Section: Methodsmentioning

confidence: 99%

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Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus

Faber¹,

Li²,

Kean

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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108

107

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Rabies remains an important public health problem with more than 95% of all human rabies cases caused by exposure to rabid dogs in areas where effective, inexpensive vaccines are unavailable. Because of their ability to induce strong innate and adaptive immune responses capable of clearing the infection from the CNS after a single immunization, live-attenuated rabies virus (RV) vaccines could be particularly useful not only for the global eradication of canine rabies but also for late-stage rabies postexposure prophylaxis of humans. To overcome concerns regarding the safety of live-attenuated RV vaccines, we developed the highly attenuated triple RV G variant, SPBAANGAS-GAS-GAS. In contrast to most attenuated recombinant RVs generated thus far, SPBAANGAS-GAS-GAS is completely nonpathogenic after intracranial infection of mice that are either developmentally immunocompromised (e.g., 5-day-old mice) or have inherited deficits in immune function (e.g., antibody production or type I IFN signaling), as well as normal adult animals. In addition, SPBAANGAS-GAS-GAS induces immune mechanisms capable of containing a CNS infection with pathogenic RV, thereby preventing lethal rabies encephalopathy. The lack of pathogenicity together with excellent immunogenicity and the capacity to deliver immune effectors to CNS tissues makes SP-BAANGAS-GAS-GAS a promising vaccine candidate for both the preexposure and postexposure prophylaxis of rabies.blood-brain barrier permeability ͉ live-attenuated rabies virus vaccine ͉ postexposure treatment R abies causes an estimated 55,000 human deaths globally each year, 23,750 of which occur in Africa (1). Moreover, 11 million people undergo rabies postexposure prophylaxis (PEP) worldwide each year. Rabies is a zoonotic disease with dogs remaining the principal host in Asia, parts of America, and large parts of Africa, and rabid dogs are the cause of most human rabies cases (2). Between 30% to 60% of the victims of dog bites are children under the age of 15 (3). Inappropriate dog vaccination programs, limited access to vaccination, and postexposure treatment of individuals that have been exposed to rabid dogs are major problems in developing countries.Rabies virus (RV), a negative-stranded RNA virus of the rhabdoviridae family, has a relatively simple, modular genome that encodes 5 structural proteins: a RNA-dependent RNA polymerase (L), a nucleoprotein (N), a phosphorylated protein (P), a matrix protein (M), and an external surface glycoprotein (G). The N, P, and L together with the genomic RNA form the ribonucleoprotein complex (RNP). The main feature of rabies virus is neuroinvasiveness, which refers to its unique ability to invade the CNS from peripheral sites. Virus uptake, axonal transport, transsynaptic spread, and the rate of viral replication are key factors that determine the neuroinvasiveness of a RV (4-7). The regulation of viral replication also appears to be one of the important mechanisms contributing to RV pathogenesis. Pathogenic RV strains replicate at a lower rate than atten...

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Section: Methodsmentioning

confidence: 99%

“…The G containing both mutations has been designated as GAS. Using the GAS gene, the single and double GAS RV variants, SPBNGAS and SPBNGAS-GAS, respectively, were constructed (10,12). The introduction of a second G gene significantly improves the efficacy of the vaccine by enhancing its immunogenicity through higher expression of G (13).…”

mentioning

confidence: 99%

Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus

Faber¹,

Li²,

Kean

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

108

107

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“…Previous results indicate that both murine and human dendritic cells can be infected and activated by RABV (19,20,34), and such cells are widely used to study inflammasome activation. Therefore, we first determined whether IL-1␤ was activated and secreted in BMDCs from mice after infection with RABV.…”

Section: Il-1␤ Is Secreted After Rabv Infectionmentioning

confidence: 99%

“…RABV activates antiviral immune responses in BMDCs via the adaptor protein IPS-1 following recognition by RIG-I and MDA5 (20). It has been previously shown that IPS-1-mediated signaling is capable of activating the NF-B signaling cascade following infection with RABV (19,20). Furthermore, transcription of pro-IL-1␤ is NF-B dependent (39).…”

Section: Il-1␤ Is Secreted After Rabv Infectionmentioning

confidence: 99%

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Rabies Virus Is Recognized by the NLRP3 Inflammasome and Activates Interleukin-1β Release in Murine Dendritic Cells

Lawrence

Hudacek

Zoete

et al. 2013

J Virol

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Inflammasome activation is important for the development of an effective host defense against many pathogens, including RNA viruses. However, the mechanism by which the inflammasome recognizes RNA viruses and its role in rabies virus (RABV) pathogenicity and immunogenicity remain poorly defined. To determine the function of the inflammasome in response to RABV infection, we infected murine bone marrow-derived dendritic cells (BMDCs) with RABV. Our results indicate that the infection of BMDCs with RABV induces both the production of pro-interleukin-1␤ (pro-IL-1␤) and its processing, resulting in the secretion of active IL-1␤ through activation of the NLRP3-, ASC-, and caspase-1-dependent inflammasome. As previously shown for the induction of type I interferon by RABV, the induction of pro-IL-1␤ also depends upon IPS-1. We demonstrate that both the production of pro-IL-1␤ and activation of the inflammasome require viral replication. We also demonstrate that increased viral replication in BMDCs derived from IFNAR-deficient mice resulted in significantly more IL-1␤ release. Additionally, IL-1 receptor-deficient mice show an increase in RABV pathogenicity. Taken together, these results indicate an important role of the inflammasome in innate immune recognition of RABV.

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Wild-type rabies virus phosphoprotein is associated with viral sensitivity to type I interferon treatment

Niu¹,

Tang

Tseggai³

et al. 2013

Arch Virol

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Rabies virus (RABV) is a single-stranded, negative-sense RNA virus that causes a fatal neurological disease in humans and animals. Our previous studies have shown that lab-adapted, but not wild-type (wt), RABV enhances innate immune responses including type I interferon (IFN) and chemokines. To determine if treatment with type I IFN can inhibit RABV infection, mouse neuroblastoma and baby hamster kidney cells were treated with IFN-α before being infected with lab-adapted or wt RABV. It was found that lab-adapted, but not the wt, RABV was able to replicate in IFN-α-pretreated cells. To determine the genes in wt RABV that confer sensitivity to IFN-α treatment, the P and the glycoprotein (G) genes from the wt RABV were used to replace the respective genes in the lab-adapted RABV. The results revealed that it is the P, not the G, gene that is associated with IFN sensitivity. Further studies have identified the regions containing the self-association domain (residues 59-139) and the C-terminal (residue 175-297) region on the P that might be associated with IFN sensitivity. The expression of ISGs, such as ISG15, ISG56, PKR, OAS-1G, was also investigated and found to be greatly increased in wt, but not in lab-adapted RABV-infected cells. It is possible that the P protein from the lab-adapted RABV can interfere with the downstream events in the interferon-signaling cascade.

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Infection of monocytes or immature dendritic cells (DCs) with an attenuated rabies virus results in DC maturation and a strong activation of the NFκB signaling pathway

Cited by 41 publications

References 26 publications

Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus

Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus

Rabies Virus Is Recognized by the NLRP3 Inflammasome and Activates Interleukin-1β Release in Murine Dendritic Cells

Wild-type rabies virus phosphoprotein is associated with viral sensitivity to type I interferon treatment

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