Pre- and post-exposure safety and efficacy of attenuated rabies virus vaccines are enhanced by their expression of IFNγ

Barkhouse, Darryll A.; Faber, Milosz; Hooper, D. Craig

doi:10.1016/j.virol.2014.10.025

Cited by 13 publications

(9 citation statements)

References 30 publications

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“…While there is evidence of a mechanism that transiently allows peripheral antibody to reach the CNS during infection of normal mice with attenuated RABV (38), we do not know whether or not this is operative in T-bet −/− mice and the kinetics of antibody accumulation in sera do not entirely parallel virus clearance from the CNS of these animals. On the other hand, the production of IFN-γ in CNS tissues has been found to strongly inhibit attenuated RABV replication independently of antibody, likely through the enhanced expression of innate antiviral agents (22). IFN-α expression was most closely related to IFN-γ-induced antiviral effects while the induction of IFN-β appeared to be more a consequence of viral replication (23).…”

Section: Discussionmentioning

confidence: 99%

“…First, cells producing IFN-γ control virus replication, evidently through the enhanced induction of type 1 interferons and other innate antiviral mechanisms (22, 23). This explains why mice with T cells but no functional B cells can control attenuated RABV infection and survive for extended periods of time while mice lacking both T and B cells succumb (24).…”

Section: Introductionmentioning

confidence: 99%

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T-bet Is Required for the Rapid Clearance of Attenuated Rabies Virus from Central Nervous System Tissue

Lebrun

Portocarrero

Kean

et al. 2015

The Journal of Immunology

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Much of our understanding of central nervous system (CNS) immunity has been gained from models involving pathological inflammation. Attenuated rabies viruses (RABV) are unique tools to study CNS immunity in the absence of conventional inflammatory mechanisms, as they spread from the site of inoculation to the CNS trans-axonally, thereby bypassing the blood-brain barrier (BBB), and are cleared without neutrophil or monocyte infiltration. To better understand the role of CD4 T cell subsets in the clearance of the virus from CNS tissues we examined the development of antiviral immunity in wild type (WT) and T-bet knock-out mice (T-bet−/−), which lack Th1 cells. Early control of RABV replication in the CNS tissues of WT mice is associated with the production of IFNγ, with antiviral effects likely mediated through the enhanced expression of type I interferons. Interestingly, IFN-α and −γ are overexpressed in the infected T-bet−/− by comparison with WT CNS tissues and the initial control of RABV infection is similar. Ultimately, attenuated RABV are cleared from the CNS tissues of WT mice by antibody locally produced by the activities of infiltrating T and B cells. While T and B cell infiltration into the CNS of infected T-bet−/− mice is comparable, their activities are not, the consequence being delayed, low level antibody production and prolonged RABV replication. More importantly, neither T-bet−/− mice immunized with an attenuated virus, nor WT mice with Th2 RABV-specific immunity induced by immunization with inactivated virus, are protected, in the long term, against challenge with a pathogenic RABV.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

T-bet Is Required for the Rapid Clearance of Attenuated Rabies Virus from Central Nervous System Tissue

Lebrun

Portocarrero

Kean

et al. 2015

The Journal of Immunology

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“…Rabies is a public health threat that causes more than 59,000 human deaths around the world each year, and most of these deaths occur in the developing countries of Asia and Africa (1,2). Globally, over 3 billion humans are threatened with exposure to rabies because they live in areas where rabies is endemic in domestic or wild animals (3).…”

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confidence: 99%

Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination

Zhou

Luo

et al. 2017

J Virol

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Rabies continues to present a public health threat in most countries of the world. The most efficient way to prevent and control rabies is to implement vaccination programs for domestic animals. However, traditional inactivated vaccines used in animals are costly and have relatively low efficiency, which impedes their extensive use in developing countries. There is, therefore, an urgent need to develop single-dose and long-lasting rabies vaccines. However, little information is available regarding the mechanisms underlying immunological memory, which can broaden humoral responses following rabies vaccination. In this study, a recombinant rabies virus (RABV) that expressed murine interleukin-7 (IL-7), referred to here as rLBNSE-IL-7, was constructed, and its effectiveness was evaluated in a mouse model. rLBNSE-IL-7 induced higher rates of T follicular helper (Tfh) cells and germinal center (GC) B cells from draining lymph nodes (LNs) than the parent virus rLBNSE. Interestingly, rLBNSE-IL-7 improved the percentages of long-lived memory B cells (Bmem) in the draining LNs and plasma cells (PCs) in the bone marrow (BM) for up to 360 days postimmunization (dpi). As a result of the presence of the long-lived PCs, it also generated prolonged virus-neutralizing antibodies (VNAs), resulting in better protection against a lethal challenge than that seen with rLBNSE. Moreover, consistent with the increased numbers of Bmem and PCs after a boost with rLBNSE, rLBNSE-IL-7-immunized mice promptly produced a more potent secondary anti-RABV neutralizing antibody response than rLBNSE-immunized mice. Overall, our data suggest that overexpressing IL-7 improved the induction of long-lasting primary and secondary antibody responses post-RABV immunization.IMPORTANCE Extending humoral immune responses using adjuvants is an important method to develop long-lasting and efficient vaccines against rabies. However, little information is currently available regarding prolonged immunological memory post-RABV vaccination. In this study, a novel rabies vaccine that expressed murine IL-7 was developed. This vaccine enhanced the numbers of Tfh cells and the GC responses, resulting in upregulated quantities of Bmem and PCs. Moreover, we found that the long-lived PCs that were elicited by the IL-7-expressing recombinant virus (rLBNSE-IL-7) were able to sustain VNA levels much longer than those elicited by the parent rLBNSE virus. Upon reexposure to the pathogen, the longevous Bmem, which maintained higher numbers for up to 360 dpi with rLBNSE-IL-7 compared to rLBNSE, could differentiate into antibody-secreting cells, resulting in rapid and potent secondary production of VNAs. These results suggest that the expression of IL-7 is beneficial for induction of potent and long-lasting humoral immune responses.KEYWORDS IL-7, humoral immunity, rabies virus

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“…Further investigation using knockout mice unable to signal through the type I IFN receptor indicated that the recombinant RABV expressing IFN-g strongly attenuates the pathogenicity via induction of type I IFN [68] . A subsequent study found that the incorporation of the murine IFN-g gene in a highly attenuated GAS backbone can enhance safety and immunogenicity [69] .…”

Section: Evidence That Rabies Virus Expression Of Chemokine/cytokine mentioning

confidence: 99%

Critical roles of chemokines and cytokines in antiviral innate immune responses during rabies virus infection

Huang¹,

Gnanadurai²,

Fu³

2017

Front. Agr. Sci. Eng.

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The innate immune response is the first line of defense against viral invasion and pro-inflammatory chemokines and cytokines have a critical function in the innate immune responses against virus infections. The ability of a rabies virus (RABV) to induce the expression of chemokines and cytokines can lead to viral clearance from the central nervous system (CNS), whereas the ability to evade such expression and activation contributes to virulence and pathogenicity. In this review, the crucial contribution of chemokines/cytokines to clearing RABV from the CNS is discussed, including recruiting leukocytes into the CNS, enhancement of blood brain barrier permeability and activation of various immune cells that are essential for viral clearance. In addition, recombinant RABV expressing cytokines and chemokines can induce elevated innate and adaptive immune responses which result in clearing an established wild-type RABV infection in the CNS.

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Pre- and post-exposure safety and efficacy of attenuated rabies virus vaccines are enhanced by their expression of IFNγ

Cited by 13 publications

References 30 publications

T-bet Is Required for the Rapid Clearance of Attenuated Rabies Virus from Central Nervous System Tissue

T-bet Is Required for the Rapid Clearance of Attenuated Rabies Virus from Central Nervous System Tissue

Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination

Critical roles of chemokines and cytokines in antiviral innate immune responses during rabies virus infection

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