Ambivalent Role of the Innate Immune Response in Rabies Virus Pathogenesis

Chopy, Damien; Pothlichet, Julien; Lafage, Mireille; Mégret, Françoise; Fiette, Laurence; Si‐Tahar, Mustapha; Lafon, Monique

doi:10.1128/jvi.00302-11

Cited by 52 publications

(42 citation statements)

References 56 publications

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“…In contrast, a residual IFN production in the NS might favor the neuronotropism of RABV by avoiding the infection of glial cells. Alternatively, the pulse of IFN-β produced by the infected neurons could stimulate IFNdependent genes such as B7-H1, a protein shown to be expressed into the RABV-infected brain and to favor RABV infection (Chopy et al 2011;Lafon et al 2008). Such a role of IFN in RABV pathogenesis will deserve further study.…”

Section: Rabv Virulence Relies On Several Factors: Among Others Rabvmentioning

confidence: 97%

“…The N protein limits RIG-I signaling (Masatani et al 2010a, c), whereas the P protein inhibits IRF3 phosphorylation (Brzozka et al 2005;Rieder et al 2011), suppresses STAT1 nuclear translocation Vidy et al 2007), and sequesters in the cytoplasm an antiviral protein, the promyelocytic leukemia (PML) protein . Despite these evasive mechanisms, it has been observed that human post-mitotic neurons infected with RABV still trigger type I IFN responses in the early stages of infection ) and that IFN is still expressed in the NS as the infection progresses (Chopy et al 2011;Johnson et al 2006;Lafon et al 2008). This addresses the question of the role of this residual IFN in the pathogenesis of RABV.…”

Section: Introductionmentioning

confidence: 93%

“…(Prehaud et al 2010) and RABVescapes adaptive immunity (Baloul et al 2004;Galelli et al 2000;Lafon 2008;Lafon et al 2008). The ability of RABV to dampen the host innate immune response has been suspected to be an additional arm of the evasion strategy of RABV (Chopy et al 2011;Wang et al 2005). Here, we investigated the role of the type I IFN response on RABV infection both in vitro and in vivo, using a RABV strain causing fatal encephalitis after an intramuscular injection into the hind limb-a route mimicking a natural infection-and two mouse models lacking IFNAR: conventional IFNAR −/− and the newly described NesCre ( +/− ) IFNAR ( flox/flox ) mouse with a deficiency of IFNR restricted to the CNS (Detje et al 2009).…”

Section: Role Of the Type I Ifn Signaling On Rabv Infection In Primarmentioning

confidence: 99%

“…Disease progression was evaluated by scoring clinical signs and mortality as previously described (Chopy et al 2011) and as follows: 0=normal mice, 1= ruffled fur, 2=one paralyzed hind leg, 3=two paralyzed hind legs and hunched back, 4=tetraplegia (defined as the total loss of mobility), and 5=death (mice were sacrificed when moribund). Data were presented as a cumulative clinical score (the individual clinical score for each mouse was added) and as a mortality curve.…”

Section: Micementioning

confidence: 99%

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The type I interferon response bridles rabies virus infection and reduces pathogenicity

et al. 2011

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Rabies virus (RABV) is a neurotropic virus transmitted by the bite of an infected animal that triggers a fatal encephalomyelitis. During its migration in the nervous system (NS), RABV triggers an innate immune response, including a type I IFN response well known to limit viral infections. We showed that although the neuroinvasive RABV strain CVS-NIV dampens type I IFN signaling by inhibiting IRF3 phosphorylation and STAT2 translocation, an early and transient type I IFN response is still triggered in the infected neuronal cells and NS. This urged us to investigate the role of type I IFN on RABV infection. We showed that primary mouse neurons (DRGs) of type I IFN(α/β) receptor deficient mice (IFNAR(-/-) mice) were more susceptible to RABV than DRGs of WT mice. In addition, exogenous type I IFN is partially efficient in preventing and slowing down infection in human neuroblastoma cells. Intra-muscular inoculation of type I IFNAR deficient mice [IFNAR(-/-) mice and NesCre ((+/-)) IFNAR ((flox/flox)) mice lacking IFNAR in neural cells of neuroectodermal origin only] with RABV reveals that the type I IFN response limits RABV dissemination in the inoculated muscle, slows down invasion of the spinal cord, and delays mortality. Thus, the type I IFN which is still produced in the NS during RABV infection is efficient enough to reduce neuroinvasiveness and pathogenicity and partially protect the host from fatal infection.

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Section: Rabv Virulence Relies On Several Factors: Among Others Rabvmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 93%

Section: Role Of the Type I Ifn Signaling On Rabv Infection In Primarmentioning

confidence: 99%

Section: Micementioning

confidence: 99%

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The type I interferon response bridles rabies virus infection and reduces pathogenicity

et al. 2011

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“…The expression of TLR-3 was more strongly elevated in the ERA-infected JAWS II cells than in the CVS-infected JAWS II cells, when examined flow cytometry (Figure 3). It is well known that the type I IFN response controls tissue tropism and pathogenicity during viral infection processes (Chopy et al 2011). As well as analyzing the expression of MHC and costimulatory molecules after RABV infection, we examined the production of the type I IFNs, IFN-α and -β, in RABV-infected DCs using an ELISA.…”

Section: Resultsmentioning

confidence: 99%

Passive carriage of rabies virus by dendritic cells

et al. 2013

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The rabies virus (RABV) is highly neurotropic and it uses evasive strategies to successfully evade the host immune system. Because rabies is often fatal, understanding the basic processes of the virus-host interactions, particularly in the initial events of infection, is critical for the design of new therapeutic approaches to target RABV. Here, we examined the possible role of dendritic cells (DCs) in the transmission of RABV to neural cells at peripheral site of exposure. Viral replication only occurred at a low level in the DC cell line, JAWS II, after its infection with either pathogenic RABV (CVS strain) or low-pathogenic RABV (ERA strain), and no progeny viruses were produced in the culture supernatants. However, both viral genomic RNAs were retained in the long term after infection and maintained their infectivity. The biggest difference between CVS and ERA was in their ability to induce type I interferons. Although the ERA-infected JAWS II cells exhibited cytopathic effect and were apparently killed by normal spleen cells in vitro, the CVS-infected JAWS II cells showed milder cytopathic effect and less lysis when cocultured with spleen cells. Strongly increased expression of major histocompatibility complex classes I, costimulatory molecules (CD80 and CD86), type I interferons and Toll- like receptor 3, and was observed only in the ERA-inoculated JAWS II cells and not in those inoculated with CVS. During the silencing of the cellular immune response in the DCs, the pathogenic CVS strain cryptically maintained an infectious viral genome and was capable of transmitting infectious RABV to permissive neural cells. These findings demonstrate that DCs may play a role in the passive carriage of RABV during natural rabies infections.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-2-419) contains supplementary material, which is available to authorized users.

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Neuroimmunology of rabies: New insights into an ancient disease

Bastos,

Pacheco,

Rodrigues

et al. 2023

Journal of Medical Virology

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Rabies is an ancient neuroinvasive viral (genus Lyssavirus, family Rhabdoviridae) disease affecting approximately 59,000 people worldwide. The central nervous system (CNS) is targeted, and rabies has a case fatality rate of almost 100% in humans and animals. Rabies is entirely preventable through proper vaccination, and thus, the highest incidence is typically observed in developing countries, mainly in Africa and Asia. However, there are still cases in European countries and the United States. Recently, demographic, increasing income levels, and the coronavirus disease 2019 (COVID‐19) pandemic have caused a massive raising in the animal population, enhancing the need for preventive measures (e.g., vaccination, surveillance, and animal control programs), postexposure prophylaxis, and a better understanding of rabies pathophysiology to identify therapeutic targets, since there is no effective treatment after the onset of clinical manifestations. Here, we review the neuroimmune biology and mechanisms of rabies. Its pathogenesis involves a complex and poorly understood modulation of immune and brain functions associated with metabolic, synaptic, and neuronal impairments, resulting in fatal outcomes without significant histopathological lesions in the CNS. In this context, the neuroimmunological and neurochemical aspects of excitatory/inhibitory signaling (e.g., GABA/glutamate crosstalk) are likely related to the clinical manifestations of rabies infection. Uncovering new links between immunopathological mechanisms and neurochemical imbalance will be essential to identify novel potential therapeutic targets to reduce rabies morbidity and mortality.

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Ambivalent Role of the Innate Immune Response in Rabies Virus Pathogenesis

Cited by 52 publications

References 56 publications

The type I interferon response bridles rabies virus infection and reduces pathogenicity

The type I interferon response bridles rabies virus infection and reduces pathogenicity

Passive carriage of rabies virus by dendritic cells

Neuroimmunology of rabies: New insights into an ancient disease

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