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Pathophysiology of human paralytic rabies

  • Mini-Review—The Rabies Virus
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Abstract

Furious rabies is a well-recognized clinical disorder in humans but the paralytic form is not as easily identified. The mechanisms responsible for the weakness and longer survival periods are not clear. Several hypotheses have been proposed, including rabies virus variants associated with a particular vector, location of wounds, incubation period, influence of prior rabies vaccination, and virus localization in the central nervous system (CNS). However, none of these have been substantiated. Regarding molecular analyses of rabies viruses isolated from both furious and paralytic rabies patients, only minor genetic variations with no specific patterns in glyco-(G), phospho-(P), and nucleoprotein (N) sequences have been identified and arginine 333 in G protein was present in all samples. Regional distribution of rabies virus antigen in rabies patients whose survival periods were 7 days or less and magnetic resonance imaging (MRI) of the CNS indicated brainstem and spinal cord as predilection sites regardless of clinical presentations. There are clinical, electrophysiological, and pathological indications that peripheral nerve dysfunction is responsible for weakness in paralytic rabies whereas in furious rabies, even in the absence of clinical weakness, abundant denervation potentials with normal sensory nerve conduction studies and proximal motor latencies suggest anterior horn cell dysfunction. The lack of cellular immunity to rabies virus antigen accompanied by an absence of cerebrospinal fluid (CSF) rabies neutralizing antibody in most paralytic rabies patients may argue against role of an immune response against rabies virus—positive axons. Aberrant immune responses to peripheral nerve antigen, in particular those mediated by one or more cellular-dependent mechanisms, may be involved as is supported by the absence of putative anti-ganglioside antibodies commonly found in immune-mediated peripheral nerve diseases. Longer survival period in paralytic rabies may possibly be related to currently unidentified mechanism(s) on neuronal gene expression, required for virus transcription/replication and for maintaining neuronal survival.

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References

  • Blancou J, Andral B, Andral L (1980). A model in mice for the study of the early death phenomenon after vaccination and challenge with rabies virus. J Gen Virol 50: 433–435.

    Article  CAS  PubMed  Google Scholar 

  • Ceccaldi PE, Marquette C, Weber P, Gourmelon P, Tsiang H (1996). Ionizing radiation modulates the spread of an apathogenic rabies virus in mouse brain. Int J Radiat Biol 70: 69–75.

    Article  CAS  PubMed  Google Scholar 

  • Ceccaldi PE, Valtorta F, Braud S, Hellio R, Tsiang H (1997). Alteration of the actin-based cytoskeleton by rabies virus. J Gen Virol 78: 2831–2835.

    CAS  PubMed  Google Scholar 

  • Chard DT, Griffin CM, Parker GJ, Kapoor R, Thompson AJ, Miller DH (2002). Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain 125: 327–337.

    Article  CAS  PubMed  Google Scholar 

  • Chopra JS, Banerjee A, Murthy JMK, Pal SR (1980). Paralytic rabies: a clinicopathological study. Brain 103: 789–802.

    Article  CAS  PubMed  Google Scholar 

  • Dumrongphol H, Srikiatkhachorn A, Hemachudha T, Kotchabhakdi N, Govitrapong P (1996). Alteration of muscarinic acetylcholine receptors in rabies viral-infected dog brains. J Neurol Sci 137: 1–6.

    Article  CAS  PubMed  Google Scholar 

  • Gamaleia N (1887). Etude sur la rage paralytique chez L’homme. Ann Inst Pasteur (Paris) 1: 63–83.

    Google Scholar 

  • Gorson K, Ropper A, Muriello M, Blair R (1996). Prospective evaluation of MRI lumbosacral nerve root enhancement in acute Guillain-Barré syndrome. Neurology 47: 813–817.

    CAS  PubMed  Google Scholar 

  • Gorson KC, Ropper AH (2001). Nonpoliovirus poliomyelitis simulating Guillain-Barré syndrome. Arch Neurol 58: 1460–1464.

    Article  CAS  PubMed  Google Scholar 

  • Gran B, Hemmer B, Vergelli M, McFarland HF, Martin R (1999). Molecular mimicry and multiple sclerosis: degenerate T-cell recognition and the induction of autoimmunity. Ann Neurol 45: 559–567.

    Article  CAS  PubMed  Google Scholar 

  • Griffin JW, Li CY, Ho TW, Tian M, Gao CY, Xue P, Mishu B, Cornblath DR, Macko C, McKhann GM, Asbury AK (1996). Pathology of the motor-sensory axonal Guillain-Barré syndrome. Ann Neurol 39: 17–28.

    Article  CAS  PubMed  Google Scholar 

  • Guigoni C, Coulon P (2002). Rabies virus is not cytolytic for rat spinal motoneurons in vitro. J NeuroVirol 8: 306–317.

    Article  PubMed  Google Scholar 

  • Hafer-Macko C, Hsieh ST, Li CY, Ho TW, Sheikh K, Cornblath DR, McKhann GM, Asbury AK, Griffin JW (1996a). Acute motor axonal neuropathy: an antibody-mediated attack on axolemma. Ann Neurol 40: 635–644.

    Article  CAS  PubMed  Google Scholar 

  • Hafer-Macko CE, Sheikh KA, Li CY, Ho TW, Cornblath DR, McKhann GM, Asbury AK, Griffin JW (1996b). Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy. Ann Neurol 39: 625–635.

    Article  CAS  PubMed  Google Scholar 

  • Hemachudha T (1989). Rabies. In: Handbook of clinical neurology viral disease. Vinken P, Bruyn G, Klawans H (eds). Amsterdam: Elsevier Science Publishers, pp 383–404.

    Google Scholar 

  • Hemachudha T (1994). Human rabies: clinical aspects, pathogenesis, and potential therapy. Curr Top Microbiol Immunol 187: 121–143.

    CAS  PubMed  Google Scholar 

  • Hemachudha T, Laothamatas J, Rupprecht CE (2002). Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol 1: 101–109.

    Article  PubMed  Google Scholar 

  • Hemachudha T, Mitrabhakdi E (2000). Rabies. In: Infectious diseases of the nervous system. Davis L, Kennedy PGE (eds). Oxford: Butterworth-Heinemann, pp 401–444.

    Google Scholar 

  • Hemachudha T, Panpanich T, Phanuphak P, Manatsathit S, Wilde H (1993). Immune activation in human rabies. Trans R Soc Trop Med Hyg 87: 106–108.

    Article  CAS  PubMed  Google Scholar 

  • Hemachudha T, Phanuphak P, Sriwanthana B, Manutsathit S, Phanthumchinda K, Siriprasomsup W, Ukachoke C, Rasameechan S, Kaoroptham S (1988). Immunologic study of human encephalitic and paralytic rabies. Preliminary report of 16 patients. Am J Med 84: 673–677.

    Article  CAS  PubMed  Google Scholar 

  • Hemachudha T, Phuapradit P (1997). Rabies. Curr Opin Neurol 10: 260–267.

    Article  CAS  PubMed  Google Scholar 

  • Hemachudha T, Rupprecht C (2004). Rabies. In: Principle of neurological infectious diseases. Roos K (ed). New York: McGraw Hill, in press.

    Google Scholar 

  • Hemachudha T, Sunsaneewitayakul B, Mitrabhakdi E, Suankratay C, Laothamathas J, Wacharapluesadee S, Khawplod P, Wilde H (2003a). Paralytic complications following intravenous rabies immune globulin treatment in a patient with furious rabies. Int J Infect Dis 7: 76–77.

    Article  PubMed  Google Scholar 

  • Hemachudha T, Wacharapluesadee S, Lumlertdaecha B, Orciari LA, Rupprecht CE, La-Ongpant M, Juntrakul S, Denduangboripant J (2003b). Sequence analysis of rabies virus in humans exhibiting encephalitic or paralytic rabies. J Infect Dis 188: 960–966.

    Article  CAS  PubMed  Google Scholar 

  • Iwasaki Y, Gerhard W, Clark HF (1977). Role of host immune response in the development of either encephalitic or paralytic disease after experimental rabies infection in mice. Infect Immun 18: 220–225.

    CAS  PubMed  Google Scholar 

  • Jackson A (2002). Human disease. In: Rabies. Jackson A, Wunner WH (eds). Amsterdam: Academic Press, pp 219–244.

    Google Scholar 

  • Kasempimolporn S, Hemachudha T, Khawplod P, Manatsathit S (1991). Human immune response to rabies nucleocapsid and glycoprotein antigens, Clin Exp Immunol 84: 195–199.

    Article  CAS  PubMed  Google Scholar 

  • Kimura T, Griffin DE (2003). Extensive immune-mediated hippocampal damage in mice surviving infection with neuroadapted Sindbis virus. Virology 311: 28–39.

    Article  CAS  PubMed  Google Scholar 

  • Kissel JT, Cornblath DR, Mendell JR (2001). Guillain-Barré syndrome. In: Diagnosis and management of peripheral nerve disorders. Mendell JR, Kissel JT, Cornblath DR, (eds). New York: Oxford University Press, pp 145–172.

    Google Scholar 

  • Lanska DJ, (1992). Rabies virus, paralytic and classical. Lancet 339: 809.

    Article  CAS  PubMed  Google Scholar 

  • Laothamatas J, Hemachudha T, Mitrabhakdi E, Wanna-krairot P, Tulayadaechanont S (2003). MR imaging in human rabies. AJNR Am J Neuroradiol 24: 1102–1109.

    PubMed  Google Scholar 

  • Leis AA, Stokic DS, Polk JL, Dostrow V, Winkelmann M (2002). A poliomyelitis-like syndrome from West Nile virus infection. N Engl J Med 347: 1279–1280.

    Article  PubMed  Google Scholar 

  • Leis AA, Stokic DS, Webb RM, Slavinski SA, Fratkin J (2003). Clinical spectrum of muscle weakness in human West Nile virus infection. Muscle Nerve 28: 302–308.

    Article  PubMed  Google Scholar 

  • Li J, Loeb JA, Shy ME, Shah AK, Tselis AC, Kupski WJ, Lewis RA (2003). Asymmetric flaccid paralysis: a neuromuscular presentation of West Nile virus infection. Ann Neurol 53: 703–710.

    Article  PubMed  Google Scholar 

  • Mazarakis ND, Azzouz M, Rohll JB, Ellard FM, Wilkes FJ, Olsen AL, Carter EE, Barber RD, Baban DF, Kingsman SM, Kingsman AJ, O’Malley K, Mitrophanous KA (2001). Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. Hum Mol Genet 10: 2109–2121.

    Article  CAS  PubMed  Google Scholar 

  • McKhann GM, Cornblath DR, Griffin JW, Ho TW, Li CY, Jiang Z, Wu HS, Zhaori G, Liu Y, Jou LP, et al (1993). Acute motor axonal neuropathy: a frequent cause of acute flaccid paralysis in China. Ann Neurol 33: 333–342.

    Article  CAS  PubMed  Google Scholar 

  • Mebatsion T (2001). Extensive attenuation of rabies virus by simultaneously modifying the dynein light chain binding site in the P protein and replacing Arg333 in the G protein. J Virol 75: 11496–11502.

    Article  CAS  PubMed  Google Scholar 

  • Mitrabhakdi E, Wannakrairot P, Shuangshoti S, Laothamatas J, Susuki K, Hemachudha T (2004). Difference in neuropathogenetic mechanisms in human furious and paralytic rabies. J Neurol Sci, in press.

  • MMWR (2004). Investigation of rabies infection in organ donor and transplant recipients—Alabama, Arkansas, Oklahoma, and Texas, 2004. MMWR Morb Mort Wkly Rep 53: 586–589.

    Google Scholar 

  • Morimoto K, Hooper DC, Spitsin S, Koprowski H, Dietzschold B (1999). Pathogenicity of different rabies virus variants inversely correlates with apoptosis and rabies virus glycoprotein expression in infected primary neuron cultures. J Virol 73: 510–518.

    CAS  PubMed  Google Scholar 

  • Murphy FA (1977). Rabies pathogenesis. Arch Virol 54: 279–297.

    Article  CAS  PubMed  Google Scholar 

  • Nelson DA, Berry RG (1993). Fatal rabies associated with extensive demyelination. Arch Neurol 50: 317–323.

    CAS  PubMed  Google Scholar 

  • Odaka M, Yuki N, Yamada M, Koga M, Takemi T, Hirata K, Kuwabara S (2003). Bickerstaff’s brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome. Brain 126: 2279–2290.

    Article  PubMed  Google Scholar 

  • Ogawara K, Kuwabara S, Mori M, Hattori T, Koga M, Yuki N (2000). Axonal Guillain-Barré syndrome: relation to anti-ganglioside antibodies and Campylobacter jejuni infection in Japan. Ann Neurol 48: 624–631.

    Article  CAS  PubMed  Google Scholar 

  • Pawan J (1939). Paralysis as a clinical manifestation in human rabies. Ann Trop Med Parasitol 33: 21–29.

    Google Scholar 

  • Perrin P, Tino de Franco M, Jallet C, Fouque F, Morgeaux S, Tordo N, Colle JH (1996). The antigen-specific cell-mediated immune response in mice is suppressed by infection with pathogenic lyssaviruses. Res Virol 147: 289–299.

    Article  CAS  PubMed  Google Scholar 

  • Prabhakar BS, Nathanson N (1981). Acute rabies death mediated by antibody. Nature 290: 590–591.

    Article  CAS  PubMed  Google Scholar 

  • Prosniak M, Hooper DC, Dietzschold B, Koprowski H (2001). Effect of rabies virus infection on gene expression in mouse brain. Proc Natl Acad Sci U S A 98: 2758–2763.

    Article  CAS  PubMed  Google Scholar 

  • Prosniak M, Zborek A, Scott GS, Roy A, Phares TW, Koprowski H, Hooper DC (2003). Differential expression of growth factors at the cellular level in virus-infected brain. Proc Natl Acad Sci U S A 100: 6765–6770.

    Article  CAS  PubMed  Google Scholar 

  • Rupprecht CE, Hemachudha T (2004). Rabies. In: Infections of the central nervous system. Scheld M, Whitley RJ, Marra C (eds). Philadelphia: Lippincott Williams and Wilkins, pp 243–259.

    Google Scholar 

  • Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfin AA, Van Gerpen JA, Fleischauer A, Leis AA, Stokic DS, Petersen LR (2003a). Neurologic manifestations and outcome of West Nile virus infection. JAMA 290: 511–515.

    Article  PubMed  Google Scholar 

  • Sejvar JJ, Leis AA, Stokic DS, Van Gerpen JA, Marfin AA, Webb R, Haddad MB, Tierney BC, Slavinski SA, Polk JL, Dostrow V, Winkelmann M, Petersen LR (2003b). Acute flaccid paralysis and West Nile virus infection. Emerg Infect Dis 9: 788–793.

    PubMed  Google Scholar 

  • Sheikh K, Jackson A, Ramos-Alvarez M, Li C, Ho T, Asbury A, Griffin J (1998). Paralytic rabies: Immune attack on nerve fibres containing axonally transported viral proteins [abstract]. Neurology 501: 183.

    Google Scholar 

  • Smith JS, McCelland CL, Reid FL, Baer GM (1982). Dual role of the immune response in street rabiesvirus infection of mice. Infect Immun 35: 213–221.

    CAS  PubMed  Google Scholar 

  • Solomon T, Dung NM, Kneen R, Gainsborough M, Vaughn DW, Khanh VT (2000a). Japanese encephalitis. J Neurol Neurosurg Psychiatry 68: 405–415.

    Article  CAS  PubMed  Google Scholar 

  • Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LT, Raengsakulrach B, Loan HT, Day NP, Farrar J, Myint KS, Warrell MJ, James WS, Nisalak A, White NJ (2000b). Neurological manifestations of dengue infection. Lancet 355: 1053–1059.

    Article  CAS  PubMed  Google Scholar 

  • Solomon T, Kneen R, Dung NM, Khann VC, Thuy TT, Ha DQ, Day NP, Nisalak A, Vaughn DW, White NJ (1998). Poliomyelitis-like illness due to Japanese encephalitis virus. Lancet 351: 1094–1097.

    Article  CAS  PubMed  Google Scholar 

  • Sriwanthana B, Hemachudha T, Griffin DE, Manutsathit S, Tweardy D, Phanuphak P (1989). Lymphocyte subsets in human encephalitic and paralytic rabies. Acta Neurol Scand 80: 287–289.

    Article  CAS  PubMed  Google Scholar 

  • Sugamata M, Miyazawa M, Mori S, Spangrude GJ, Ewalt LC, Lodmell DL (1992). Paralysis of street rabies virus-infected mice is dependent on T lymphocytes. J Virol 66: 1252–1260.

    CAS  PubMed  Google Scholar 

  • Susuki K, Odaka M, Mori M, Hirata K, Yuki N (2004). Acute motor axonal neuropathy after Mycoplasma infection: evidence of molecular mimicry. Neurology 62: 949–956.

    CAS  PubMed  Google Scholar 

  • Tangchai P, Vejjajiva A (1971). Pathology of the peripheral nervous system in human rabies: a study of nine autopsy cases. Brain 94: 299–306.

    Article  CAS  PubMed  Google Scholar 

  • Tangchai P, Yenbutr D, Vejjajiva A (1970). Central nervous system lesions in human rabies. J Med Assoc Thailand 53: 471–488.

    Google Scholar 

  • Tignor GH, Shope RE, Gershon RK, Waksman BH (1974). Immunopathologic aspects of infection with Lagos bat virus of the rabies serogroup. J Immunol 112: 260–265.

    CAS  PubMed  Google Scholar 

  • Tirawatnpong S, Hemachudha T, Manutsathit S, Shuangshoti S, Phanthumchinda K, Phanuphak P (1989). Regional distribution of rabies viral antigen in central nervous system of human encephalitic and paralytic rabies. J Neurol Sci 92: 91–99.

    Article  CAS  PubMed  Google Scholar 

  • Tomonaga K (2004). Virus-induced neurobehavioral disorders: mechanisms and implications. Trends Mol Med 10: 71–77.

    Article  CAS  PubMed  Google Scholar 

  • Tuffereau C, Desmezieres E, Benejean J, Jallet C, Flamand A, Tordo N, Perrin P (2001). Interaction of lyssaviruses with the low-affinity nerve-growth factor receptor p75NTR. J Gen Virol 82: 2861–2867.

    CAS  PubMed  Google Scholar 

  • Weiland F, Cox JH, Meyer S, Dahme E, Reddehase MJ (1992). Rabies virus neuritic paralysis: immunopathogenesis of nonfatal paralytic rabies. J Virol 66: 5096–5099.

    CAS  PubMed  Google Scholar 

  • Willison HJ, Yuki N (2002). Peripheral neuropathies and anti-glycolipid antibodies. Brain 125: 2591–2625.

    Article  PubMed  Google Scholar 

  • Wunner W (2002). Rabies virus. In: Rabies. Jackson A, Wunner WH (eds). Amsterdam: Academic Press, pp 23–77.

    Google Scholar 

  • Zivadinov R, Bakshi R (2004). Role of MRI in multiple sclerosis I: inflammation and lesions. Front Biosci 9: 665–683.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine and the Molecular Biology Laboratory for Neurological Diseases, Chulalongkorn University Hospital, Bangkok, Thailand

    Thiravat Hemachudha, Supaporn Wacharapluesadee & Erawady Mitrabhakdi

  2. Queen Saovabha Memorial Institute, Thai Red Cross Society, Bangkok, Thailand

    Henry Wilde

  3. The National Institute of Infectious Diseases, Tokyo, Japan

    Kinjiro Morimoto

  4. Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA

    Richard A. Lewis

  5. Neurology Division, Department of Medicine, Chulalongkorn University Hospital, Rama 4 Road, 10330, Bangkok, Thailand

    Thiravat Hemachudha

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  1. Thiravat Hemachudha
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  2. Supaporn Wacharapluesadee
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  3. Erawady Mitrabhakdi
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  4. Henry Wilde
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  5. Kinjiro Morimoto
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  6. Richard A. Lewis
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Correspondence to Thiravat Hemachudha.

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This work was supported in part by grants from Thailand Research Fund and National Center for Genetic Engineering and Biotechnology and Thai Red Cross Society, Bangkok, Thailand.

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Hemachudha, T., Wacharapluesadee, S., Mitrabhakdi, E. et al. Pathophysiology of human paralytic rabies. Journal of NeuroVirology 11, 93–100 (2005). https://doi.org/10.1080/13550280590900409

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