Presence of Virus Neutralizing Antibodies in Cerebral Spinal Fluid Correlates with Non-Lethal Rabies in Dogs

Gnanadurai, Clement W.; Zhou, Ming; He, Wenqi; Leyson, Christina M.; Huang, Chien-Tsun; Salyards, Gregory W; Harvey, Stephen B.; Chen, Zhenhai; He, Biao; Yang, Yang; Hooper, D. Craig; Dietzchold, Berhnard; Fu, Zhen F.

doi:10.1371/journal.pntd.0002375

Cited by 30 publications

(20 citation statements)

References 29 publications

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“…The inability of wild-type (wt) RABV to induce VNA responses also has been reported in other animal species, such as mice (10), dogs (11), and skunks (12). On the other hand, experimental infection with laboratory-attenuated RABV induces VNA responses in laboratory animals (10,(13)(14)(15)(16)(17).…”

mentioning

confidence: 81%

The Inability of Wild-Type Rabies Virus To Activate Dendritic Cells Is Dependent on the Glycoprotein and Correlates with Its Low Level of theDe Novo-Synthesized Leader RNA

Yang

Huang

Gnanadurai

et al. 2015

J Virol

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Dendritic cells (DCs) are the most efficient antigen-presenting cells, playing a key role in the adaptive immune responses to viral infections. Our studies demonstrate that wild-type (wt) rabies virus (RABV) does not activate DCs. Adoptive transfer of DCs primed with wt RABV did not activate DCs, stimulate virus neutralizing antibodies (VNA), or protect recipients against challenge. However, adoptive transfer of DCs primed with laboratory-attenuated RABV resulted in DC activation, production of VNA, and protection against challenge. In vitro studies with recombinant RABV (laboratory-attenuated RABV expressing the glycoprotein or the phosphoprotein from wt RABV) demonstrate that DC activation is dependent on the glycoprotein and involves the IPS-1 pathway. Furthermore, binding to and entry into DCs by wt RABV is severely blocked, and the copy number of de novo-synthesized leader RNA was two logs lower in DCs infected with the wt than in DCs treated with laboratory-attenuated RABV. However, transient transfection of DCs with synthesized leader RNA from either wt or attenuated RABV is capable of activating DCs in a dose-dependent manner. Thus, the inability of wt RABV to activate DCs correlates with its low level of the de novo-synthesized leader RNA. IMPORTANCERabies remains a public health threat, with more than 55,000 fatalities each year around the world. Since DCs play a key role in the adaptive immune responses to viral infections, we investigated the ability of rabies virus (RABV) to activate DCs. It was found that the adoptive transfer of DCs primed with wt RABV did not activate DCs, stimulate VNA, or protect mice against lethal challenge. However, laboratory-attenuated RABV mediates the activation of DCs via the IPS-1 pathway and is glycoprotein dependent. We further show that wt RABV evades DC-mediated immune activation by inefficient binding/entry into DCs and as a result of a reduced level of de novo-synthesized leader RNA. These findings may have important implications in the development of efficient rabies vaccines. Despite the fact that rabies is one of the oldest human infectious diseases, it continues to present a public health threat by causing more than 55,000 human deaths every year around the globe (1). Its causative agent, rabies virus (RABV), belongs to the Rhabdoviridae family, and its genome encodes five structural proteins in the order of nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and RNA-dependent RNA polymerase (RdRp; also termed large protein [L]) (2). Among these, RABV G is the only viral protein that is glycosylated and exposed on the surface of the virion (3). RABV G is responsible for binding to neurospecific receptors, such as the acetylcholine receptor and neural cell adhesion molecule (NCAM), for invasion into the nervous system (4, 5). Moreover, RABV G is the only protein capable of inducing virus-neutralizing antibodies (VNA) that are protective against rabies (6-8).It has been known for a long time that most of the human rabies patient...

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confidence: 81%

The Inability of Wild-Type Rabies Virus To Activate Dendritic Cells Is Dependent on the Glycoprotein and Correlates with Its Low Level of theDe Novo-Synthesized Leader RNA

Yang

Huang

Gnanadurai

et al. 2015

J Virol

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“…Most street RABVs evade the host innate immune system and fail to induce protective virus neutralizing antibody (VNA) responses [ 13 - 16 ]. However, in some murine or dog experimental models infected with street RABVs, T cell and mononuclear cell infiltration in the CNS have been observed together with severe encephalitis in the late stage of infection [ 16 - 18 ].…”

Section: Introductionmentioning

confidence: 99%

Met-CCL5 represents an immunotherapy strategy to ameliorate rabies virus infection

Huang¹,

Jiao

Tao³

et al. 2014

J Neuroinflammation

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BackgroundInfection of rabies virus (RABV) causes central nervous system (CNS) dysfunction and results in high mortality in human and animals. However, it is still unclear whether and how CNS inflammation and immune response contribute to RABV infection.MethodsSuckling mice were intracerebrally infected with attenuated RABV aG and CTN strains, followed by examination of chemokine or cytokine production, inflammatory cell infiltration and neuron apoptosis in the brain. Furthermore, the suckling mice and adult mice that were intracerebrally infected with aG and the adult mice that were intramuscularly infected with street RABV HN10 were treated with CCL5 antagonist (Met-CCL5) daily beginning on day 2 postinfection. The survival rates and inflammation responses in the CNS of these mice were analyzed.ResultsExcessive CCL5 in the CNS was associated with CNS dysfunction, inflammation, and macrophage or lymphocyte infiltration after attenuated or street RABV infection. Administration of exogenous CCL5 induced excessive infiltration of immune cells into the CNS and enhanced inflammatory chemokine and cytokine production. Met-CCL5 treatment significantly prolonged survival time of the suckling mice inoculated with aG and adult mice infected with aG and HN10.ConclusionsThese results suggest that CCL5 in the CNS is a key regulator involved in inducing rabies encephalomyelitis. Furthermore, treatment with the CCL5 antagonist Met-CCL5 prolongs survival time of the mice infected with attenuated or street RABVs, which might represent a novel therapeutic strategy to ameliorate RABV infection.

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“…However, if clearance of the virus can be achieved before entry into the CNS, clinical infection can be avoided, leading to a subclinical or 'aborted' infection with mild or no symptoms. A number of studies have observed subclinical infections following experimental exposure with RABV, including in dogs [63,64] and mice [65,66]. In bats, the occurrence of subclinical rabies infection is particularly prevalent [67].…”

Section: Subclinical Infectionmentioning

confidence: 99%

“…However, once the virus is in the CNS, it is protected from the humoral immune response unless antibody is able to cross the blood-brain barrier (BBB). In cases in which recovery has been recorded, permeability of the BBB and the presence of antibody in the cerebrospinal fluid (CSF) have been shown to be key correlates of recovery [63,84,85,86]. As a result, in cases in which antibody is detected in the CSF of healthy individuals as well as the serum, this provides a key indication of recovery rather than subclinical infection.…”

Section: Recoverymentioning

confidence: 99%

Rabies virus-neutralising antibodies in healthy, unvaccinated individuals: What do they mean for rabies epidemiology?

et al. 2020

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Rabies has been a widely feared disease for thousands of years, with records of rabid dogs as early as ancient Egyptian and Mesopotamian texts. The reputation of rabies as being inevitably fatal, together with its ability to affect all mammalian species, contributes to the fear surrounding this disease. However, the widely held view that exposure to the rabies virus is always fatal has been repeatedly challenged. Although survival following clinical infection in humans has only been recorded on a handful of occasions, a number of studies have reported detection of rabies-specific antibodies in the sera of humans, domestic animals, and wildlife that are apparently healthy and unvaccinated. These 'seropositive' individuals provide possible evidence of exposure to the rabies virus that has not led to fatal disease. However, the variability in methods of detecting these antibodies and the difficulties of interpreting serology tests have contributed to an unclear picture of their importance. In this review, we consider the evidence for rabies-specific antibodies in healthy, unvaccinated individuals as indicators of nonlethal rabies exposure and the potential implications of this for rabies epidemiology. Our findings indicate that whilst there is substantial evidence that nonlethal rabies exposure does occur, serology studies that do not use appropriate controls and cutoffs are unlikely to provide an accurate estimate of the true prevalence of nonlethal rabies exposure.

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Presence of Virus Neutralizing Antibodies in Cerebral Spinal Fluid Correlates with Non-Lethal Rabies in Dogs

Cited by 30 publications

References 29 publications

The Inability of Wild-Type Rabies Virus To Activate Dendritic Cells Is Dependent on the Glycoprotein and Correlates with Its Low Level of theDe Novo-Synthesized Leader RNA

The Inability of Wild-Type Rabies Virus To Activate Dendritic Cells Is Dependent on the Glycoprotein and Correlates with Its Low Level of theDe Novo-Synthesized Leader RNA

Met-CCL5 represents an immunotherapy strategy to ameliorate rabies virus infection

Rabies virus-neutralising antibodies in healthy, unvaccinated individuals: What do they mean for rabies epidemiology?

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