Abstract
Junin virus antigen distribution and astrocytic reaction to prolonged infection were characterized in rat brain by the PAP technique. During the acute stage of neurologic disease following intracerebral inoculation, Junin antigen was detected in 100% of animals, strongly in most neurons but also to a much lesser degree in scattered astrocytes, dropping to 20% of rats at 540 days postinfection. Initially labeled in all brain areas, viral antigen gradually disappeared from hippocampus but persisted irregularly in cerebral cortex, basal ganglia, Purkinje cells, pons, and medulla oblongata. Such a pattern suggests that specific neuronal subpopulations, in spite of apparently unaltered cell morphology, may persistently harbor the virus, leading on occasion to a delayed neurologic syndrome. During both the acute and chronic stages of disease, a mild inflammatory exudate was observed, characterized by the presence of T and B lymphocytes, as well as macrophages and unidentified round cells. GFAP immunostaining showed increased astrocytic reaction as infection lapsed into chronicity. Corpus callosum, hippocampus, and cerebellum exhibited the sharpest reactive astrocytosis, followed by basal ganglia, pons, and medulla oblongata, whereas in cerebral cortex it was considerably less. Astrocyte activation, which failed to correlate with viral antigen presence in neurons, seems to result from a generalized condition, possibly including diffusible brain factors triggered by viral infection. Such widespread astroglial reaction may thus contribute to the outcome of the late neurologic syndrome.
Keywords: Argentine hemorrhagic fever, neurological disease, viral antigen
References
- Amaducci A, Forno KI, Eng LF (1981): Glial fibrillary acidic protein in cryogenic lesions of the rat brain. Neuroscience Letters 21: 27–32. [DOI] [PubMed] [Google Scholar]
- Bernard A, Wild TF, Tripier MF (1983): Canine distemper infection in mice: Characterization of a neuro‐adapted virus strain and its long‐term evolution in the mouse. Journal of General Virology 64: 1571–1579. [DOI] [PubMed] [Google Scholar]
- Berría MI, Lascano EF (1985): Astrocyte differentiation induced by Junin virus in rat brain cell cultures. Acta Neuropathologica 66: 233–238. [DOI] [PubMed] [Google Scholar]
- Bignami A, Dahl D (1974): Astrocyte‐protein and neuroglial differentiation. An immunofluorescent study with antibodies to the glial fibrillary acidic protein. Journal of Comparative Neurology 153: 27–38. [DOI] [PubMed] [Google Scholar]
- Bignami A, Dahl D (1976): The astroglial response to stabbing. Immunofluorescence studies with antibodies to astrocyte‐specific protein (GFA) in mammalian and submammalian vertebrates. Neuropathology and Applied Neurobiology 2: 99–110. [Google Scholar]
- de la Monte SM, Linhares AL, Travassos da Rosa APA, Pinheiro FP (1983): Immunoperoxidase detection of yellow fever after natural and experimental infections. Tropical and Geographical Medicine 35: 235–241. [PubMed] [Google Scholar]
- Eng LF, DeArmond SJ (1982): Immunocytochemical studies of astrocytes in normal development and disease In Fedoroff S, Hertz L. (eds): “Advances in Cellular Neurobiology,” Vol 3 New York: Academic Press, pp 145–171. [Google Scholar]
- Fekadu M, Chandler FW, Harrison AK (1982): Pathogenesis of rabies in dogs inoculated with an Ethiopian rabies virus strain. Immunofluorescence, histologic and ultrastructural studies of the central nervous system. Archives of Virology 71: 109–126. [DOI] [PubMed] [Google Scholar]
- Griffin DE, Hess JL, Moench TR (1987): Immune responses in the central nervous system. Toxicologic Pathology 15: 294–302. [DOI] [PubMed] [Google Scholar]
- Kato T, Fukui Y, Turriff DE, Nagakawa S, Lim R, Arnason BGW, Tanaka R (1981): Glia maturation factor in bovine brain: Partial purification and physicochemical characterization. Brain Research 212: 393–402. [DOI] [PubMed] [Google Scholar]
- Kristensson K, Holmes KV, Duchala CS, Zeller NK, Lazzarini RA, Dubois‐Dalcq M (1986): Increased levels of myelin basic protein transcript gene in virus‐induced demyelination. Nature 322: 544–547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kristensson K, Norrby E (1986): Persistence of RNA viruses in the central nervous system. Annual Review of Microbiology 40: 159–184. [DOI] [PubMed] [Google Scholar]
- Kristensson K, Orvell C, Leetsma J, Norrby E (1983): Sandai virus infection in the brains of mice: Distribution of viral antigens studied with monoclonal antibodies. Journal of Infectious Diseases 147: 297–301. [DOI] [PubMed] [Google Scholar]
- Lascano EF, Berría MI (1974): Ultrastructure of Junin virus in mouse whole brain and in mouse brain tissue cultures. Journal of Virology 14: 965–974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lascano EF, Berría MI (1983): Immunoperoxidase study of astrocytic reaction to Junin virus encephalomyelitis of mice. Acta Neuropathologica 59: 183–190. [DOI] [PubMed] [Google Scholar]
- Lascano EF, Blejer JL, Galassi NV, Nejamkis MR (1986): Brain inflammatory exudate in Junin virus‐infected rats: Its characterization by the immunoperoxidase (PAP) technique. Journal of Neuroimmunology 11: 105–116. [DOI] [PubMed] [Google Scholar]
- Latov N, Nilaver G, Zimmerman EA, Johnson WG, Silverman A‐J, Defendini R, Cote L (1979): Fibrillary astrocytes proliferate in response to brain injury. A study combining immunoperoxidase technique for glial fibrillary acidic protein and radioautography of tritiated thymidine. Developmental Biology 72: 381–384. [DOI] [PubMed] [Google Scholar]
- Lindsay RM (1986): Reactive gliosis In Fedoroff S, Vernadakis A. (eds): “Astrocytes. Cell Biology and Pathology of Astrocytes,” Vol 3 Orlando: Academic Press, pp 231–262. [Google Scholar]
- Lipkin WI, Battenburg ELF, Bloom FE, Oldstone MBA (1988): Viral infection of neurons can depress neurotransmitter mRNA levels without histologic injury. Brain Research 451: 333–339. [DOI] [PubMed] [Google Scholar]
- Ludwin SK, Kosek JC, Eng LF (1976): The topographical distribution of S‐100 and GFA proteins in the adult rat brain. An immunohistochemical study using horseradish peroxidase‐labelled antibodies. Journal of Comparative Neurology 165: 197–208. [DOI] [PubMed] [Google Scholar]
- Maiztegui JI, Fernandez NJ, de Damilano AJ (1979): Efficacy of immune plasma in treatment of Argentine hemorrhagic fever and association between treatment and a late neurologic syndrome. Lancet 2: 1216–1217. [DOI] [PubMed] [Google Scholar]
- Manuelidis L, Tesin DM, Sklaviadis T, Manuelidis EE (1987): Astrocyte gene expression in Creutzfeldt‐Jakob disease. Proceedings of the National Academy of Sciences USA 84: 5937–5941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Melcon MO, Herskovitz E (1981): Complicaciones neurológicas tardías de la Fiebre Hemorrágica Argentina. Medicina (Buenos Aires) 41: 137–145. [PubMed] [Google Scholar]
- Miller RH, Raff MC (1984): Fibrous and protoplasmic astrocytes are biochemically and developmentally distinct. Journal of Neuroscience 4: 585–592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nieto‐Sampedro M, Saneto RP, de Vellis J, Cotman CW (1985): The control of glial populations in brain: Changes in astrocytic mitogenic and morphogenic factors in response to injury. Brain Research 343: 320–328. [DOI] [PubMed] [Google Scholar]
- Oldstone MBA, Blount P, Southern PJ, Lampert PW (1986): Cytoimmunotherapy for persistent virus infection reveals a unique clearance pattern from the central nervous system. Nature 321: 239–243. [DOI] [PubMed] [Google Scholar]
- Pearson J, Mims CA (1983): Selective vulnerability of neural cells and age‐related susceptibility to Oc43 virus in mice. Archives of Virology 77: 109–118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pettmann B, Sensebrenner M, Labourdette G (1980): Isolation of a glial maturation factor from beef brain. FEBS Letters 118: 195–199. [DOI] [PubMed] [Google Scholar]
- Reier PJ (1986): Gliosis following CNS injury: The anatomy of astrocytic scars and their influences on axonal elongation In Fedoroff S, Vernadakis A. (eds): “Astrocytes. Cell Biology and Pathology of Astrocytes,” Vol 3 Orlando: Academic Press, pp 263–324. [Google Scholar]
- Rodriguez M, Buchmeier MJ, Oldstone MBA, Lampert PW (1983): Ultrastructural localization of viral antigens in the CNS of mice persistently infected with lymphocytic choriomeningitis virus (LCM). American Journal of Pathology 110: 95–100. [PMC free article] [PubMed] [Google Scholar]
- Sethi P, Lipton HL (1983): Location and distribution of virus antigen in the central nervous system of mice persistently infected with Theiler's virus. British Journal of Experimental Pathology 64: 57–65. [PMC free article] [PubMed] [Google Scholar]
- Sobue G, Pleasure D (1984): Astroglial proliferation and phenotype are modulated by neuronal plasma membrane. Brain Research 324: 175–179. [DOI] [PubMed] [Google Scholar]
- Sorensen O, Dales S (1985): In vivo and in vitro models of demyelinating disease: JHM virus in the rat central nervous system localized by in situ cDNA hibridization and immunofluorescent microscopy. Journal of Virology 56: 434–438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spriggs DR, Bronson RT, Fields BN (1983): Hemagglutinin variants of reovirus type 3 have altered central nervous system tropism. Science 226: 505–507. [DOI] [PubMed] [Google Scholar]
- Takamiya Y, Kohsaka S, Toya S, Otani M, Tsukada Y (1988): Immunohistochemical studies on the proliferation of reactive astrocytes and the expression of cytoskeletal proteins following brain injury in rats. Developmental Brain Research 38: 201–210. [DOI] [PubMed] [Google Scholar]
- Weissenbacher MC, Lascano EF, Avila MM, Berría MI (1986): Chronic neurologic disease in Junin virus‐infected rats. Journal of Medical Virology 20: 57–65. [DOI] [PubMed] [Google Scholar]