Furious Rabies after an Atypical Exposure

Wertheim, Heiman; Nguyen, Thai Quoc; Nguyen, Kieu Anh Thi; Jong, Menno D. de; Taylor, Walter R. J.; Le, Tan V.; Nguyen, Ha H; Nguyen, Hanh; Farrar, Jeremy; Horby, Peter; Nguyen, Hien

doi:10.1371/journal.pmed.1000044

Cited by 54 publications

(46 citation statements)

References 27 publications

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“…https://doi.org/10.1371/journal.ppat.1008343.g004 is likely to be associated with dysfunction in the brain [47], as it affects higher neurological functions such as behavior and cognition [48]. Furthermore, there is usually minimal spinal paralysis in the furious form, at least in the initial stages of disease.…”

Section: Discussionmentioning

confidence: 99%

Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies

et al. 2020

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Neurotropic viral infections continue to pose a serious threat to human and animal wellbeing. Host responses combatting the invading virus in these infections often cause irreversible damage to the nervous system, resulting in poor prognosis. Rabies is the most lethal neurotropic virus, which specifically infects neurons and spreads through the host nervous system by retrograde axonal transport. The key pathogenic mechanisms associated with rabies infection and axonal transmission in neurons remains unclear. Here we studied the pathogenesis of different field isolates of lyssavirus including rabies using ex-vivo model systems generated with mouse primary neurons derived from the peripheral and central nervous systems. In this study, we show that neurons activate selective and compartmentalized degeneration of their axons and dendrites in response to infection with different field strains of lyssavirus. We further show that this axonal degeneration is mediated by the loss of NAD and calpain-mediated digestion of key structural proteins such as MAP2 and neurofilament. We then analysed the role of SARM1 gene in rabies infection, which has been shown to mediate axonal self-destruction during injury. We show that SARM1 is required for the accelerated execution of rabies induced axonal degeneration and the deletion of SARM1 gene significantly delayed axonal degeneration in rabies infected neurons. Using a microfluidic-based ex-vivo neuronal model, we show that SARM1-mediated axonal degeneration impedes the spread of rabies virus among interconnected neurons. However, this neuronal defense mechanism also results in the pathological loss of axons and dendrites. This study therefore identifies a potential host-directed mechanism behind neurological dysfunction in rabies infection. This study also implicates a novel role of SARM1 mediated axonal degeneration in neurotropic viral infection.

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Section: Discussionmentioning

confidence: 99%

Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies

et al. 2020

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“…This variation on defined clinical disease has been termed 'non-classical atypical rabies'. This usually manifests with, among other neurological symptoms, neuropathic pain, focal brain stem signs and myoclonus (Wertheim et al, 2009;Hemachudha et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Pathobiology of rabies virus and the European bat lyssaviruses in experimentally infected mice

et al. 2013

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“…Human rabies cases have also been attributed to probable aerosol exposures in laboratories or airborne exposures in caves with high densities of bats (8, 9). In addition, atypical transmission through butchering and processing of rabid animals, as well as human‐to‐human transmission by organ or tissue transplantation have been reported (10, 11).…”

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confidence: 99%

Production, characterization, and antigen specificity of recombinant 62‐71‐3, a candidate monoclonal antibody for rabies prophylaxis in humans

et al. 2013

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Rabies kills many people throughout the developing world every year. The murine monoclonal antibody (mAb) 62-71-3 was recently identified for its potential application in rabies postexposure prophylaxis (PEP). The purpose here was to establish a plant-based production system for a chimeric mouse-human version of mAb 62-71-3, to characterize the recombinant antibody and investigate at a molecular level its interaction with rabies virus glycoprotein. Chimeric 62-71-3 was successfully expressed in Nicotiana benthamiana. Glycosylation was analyzed by mass spectroscopy; functionality was confirmed by antigen ELISA, as well as rabies and pseudotype virus neutralization. Epitope characterization was performed using pseudotype virus expressing mutagenized rabies glycoproteins. Purified mAb demonstrated potent viral neutralization at 500 IU/mg. A critical role for antigenic site I of the glycoprotein, as well as for two specific amino acid residues (K226 and G229) within site I, was identified with regard to mAb 62-71-3 neutralization. Pseudotype viruses expressing glycoprotein from lyssaviruses known not to be neutralized by this antibody were the controls. The results provide the molecular rationale for developing 62-71-3 mAb for rabies PEP; they also establish the basis for developing an inexpensive plant-based antibody product to benefit low-income families in developing countries.—Both, L., van Dolleweerd, C., Wright, E., Banyard, A. C., Bulmer-Thomas, B., Selden, D., Altmann, F., Fooks, A. R., Ma, J. K.-C. Production, characterization, and antigen specificity of recombinant 62-71-3, a candidate monoclonal antibody for rabies prophylaxis in humans.

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Furious Rabies after an Atypical Exposure

Abstract: Heiman Wertheim and colleagues describe the diagnosis and management of two patients who developed rabies after butchering and consuming a dog or a cat.

Cited by 54 publications

References 27 publications

Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies

Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies

Pathobiology of rabies virus and the European bat lyssaviruses in experimentally infected mice

Production, characterization, and antigen specificity of recombinant 62‐71‐3, a candidate monoclonal antibody for rabies prophylaxis in humans

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