The role of CNS immunity in the clearance of rabies virus

Main Article Content

Aurore Lebrun Douglas Craig Hooper

Abstract

Rabies is a zoonotic disease caused by the neurotropic rabies virus (RABV). In the absence of treatment the infection is nearly always fatal for the host. Extensive research aimed at better understanding RABV pathogenicity and immunogenicity has led to the characterization of a wide array of RABV strains. Comparative studies between pathogenic and attenuated RABV strains have provided insights into the mechanism by which the virus can be cleared from CNS tissues. In this context, attenuated RABV represents a unique model in which the timely development of an unconventional non-inflammatory rabies-specific neuroimmune response is the key determinant of host survival. Highly pathogenic wild-type rabies viruses have evolved strategies to evade the host immune response and spread through the maintenance of blood-brain barrier integrity and an intact neuronal network. The focus of this review is to provide a synopsis of the differences in the CNS immune responses to pathogenic and attenuated RABV strains and their relevance for the development of new treatment strategies. 

Article Details

How to Cite
LEBRUN, Aurore; HOOPER, Douglas Craig. The role of CNS immunity in the clearance of rabies virus. Medical Research Archives, [S.l.], v. 4, n. 5, sep. 2016. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/641>. Date accessed: 23 nov. 2024.
Keywords
rabies virus, CNS, immunology
Section
Review Articles

References

Abbott, N. J., Ronnback, L., & Hansson, E. (2006). Astrocyte-endothelial interactions at the blood-brain barrier. [Research Support, Non-U.S. Gov't Review]. Nat Rev Neurosci, 7(1), 41-53. doi: 10.1038/nrn1824

Adamson, P. B. (1977). The spread of rabies into Europe and the probable origin of this disease in antiquity. [Historical Article]. J R Asiat Soc GB Irel, 2, 140-144.

Albertini, A. A., Ruigrok, R. W., & Blondel, D. (2011). Rabies virus transcription and replication. [Research Support, Non-U.S. Gov't Review]. Adv Virus Res, 79, 1-22. doi: 10.1016/B978-0-12-387040-7.00001-9

Armulik, A., Abramsson, A., & Betsholtz, C. (2005). Endothelial/pericyte interactions. [Research Support, Non-U.S. Gov't Review]. Circ Res, 97(6), 512-523. doi: 10.1161/01.RES.0000182903.16652.d7

Aspelund, A., Antila, S., Proulx, S. T., Karlsen, T. V., Karaman, S., Detmar, M., . . . Alitalo, K. (2015). A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. [Research Support, Non-U.S. Gov't]. J Exp Med, 212(7), 991-999. doi: 10.1084/jem.20142290

Barkhouse, D. A., Garcia, S. A., Bongiorno, E. K., Lebrun, A., Faber, M., & Hooper, D. C. (2015). Expression of interferon gamma by a recombinant rabies virus strongly attenuates the pathogenicity of the virus via induction of type I interferon. [Research Support, N.I.H., Extramural]. J Virol, 89(1), 312-322. doi: 10.1128/JVI.01572-14

Blondel, D., Maarifi, G., Nisole, S., & Chelbi-Alix, M. K. (2015). Resistance to Rhabdoviridae Infection and Subversion of Antiviral Responses. [Research Support, Non-U.S. Gov't Review]. Viruses, 7(7), 3675-3702. doi: 10.3390/v7072794

Brzozka, K., Finke, S., & Conzelmann, K. K. (2005). Identification of the rabies virus alpha/beta interferon antagonist: phosphoprotein P interferes with phosphorylation of interferon regulatory factor 3. [Research Support, Non-U.S. Gov't]. J Virol, 79(12), 7673-7681. doi: 10.1128/JVI.79.12.7673-7681.2005

Caillet-Saguy, C., Maisonneuve, P., Delhommel, F., Terrien, E., Babault, N., Lafon, M., . . . Wolff, N. (2015). Strategies to interfere with PDZ-mediated interactions in neurons: What we can learn from the rabies virus. [Research Support, Non-U.S. Gov't Review]. Prog Biophys Mol Biol, 119(1), 53-59. doi: 10.1016/j.pbiomolbio.2015.02.007

Chai, Q., He, W. Q., Zhou, M., Lu, H., & Fu, Z. F. (2014). Enhancement of blood-brain barrier permeability and reduction of tight junction protein expression are modulated by chemokines/cytokines induced by rabies virus infection. [Research Support, N.I.H., Extramural]. J Virol, 88(9), 4698-4710. doi: 10.1128/JVI.03149-13

Chai, Q., She, R., Huang, Y., & Fu, Z. F. (2015). Expression of neuronal CXCL10 induced by rabies virus infection initiates infiltration of inflammatory cells, production of chemokines and cytokines, and enhancement of blood-brain barrier permeability. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]. J Virol, 89(1), 870-876. doi: 10.1128/JVI.02154-14

Charlton, K. M., & Casey, G. A. (1979). Experimental rabies in skunks: immunofluorescence light and electron microscopic studies. Lab Invest, 41(1), 36-44.

Daneman, R. (2012). The blood-brain barrier in health and disease. [Review]. Ann Neurol, 72(5), 648-672. doi: 10.1002/ana.23648

Dietrich, J. B. (2002). The adhesion molecule ICAM-1 and its regulation in relation with the blood-brain barrier. [Review]. J Neuroimmunol, 128(1-2), 58-68.
Dietzschold, B. (1993). Antibody-mediated clearance of viruses from the mammalian central nervous system. [Research Support, U.S. Gov't, P.H.S. Review]. Trends Microbiol, 1(2), 63-66.

Dietzschold, B., Wunner, W. H., Wiktor, T. J., Lopes, A. D., Lafon, M., Smith, C. L., & Koprowski, H. (1983). Characterization of an antigenic determinant of the glycoprotein that correlates with pathogenicity of rabies virus. [Research Support, U.S. Gov't, P.H.S.]. Proc Natl Acad Sci U S A, 80(1), 70-74.

Djuretic, I. M., Levanon, D., Negreanu, V., Groner, Y., Rao, A., & Ansel, K. M. (2007). Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]. Nat Immunol, 8(2), 145-153. doi: 10.1038/ni1424

Faber, M., Faber, M. L., Li, J., Preuss, M. A., Schnell, M. J., & Dietzschold, B. (2007). Dominance of a nonpathogenic glycoprotein gene over a pathogenic glycoprotein gene in rabies virus. [Comparative Study Research Support, N.I.H., Extramural]. J Virol, 81(13), 7041-7047. doi: 10.1128/JVI.00357-07

Faber, M., Li, J., Kean, R. B., Hooper, D. C., Alugupalli, K. R., & Dietzschold, B. (2009). Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus. [Research Support, N.I.H., Extramural]. Proc Natl Acad Sci U S A, 106(27), 11300-11305. doi: 10.1073/pnas.0905640106

Faber, M., Pulmanausahakul, R., Hodawadekar, S. S., Spitsin, S., McGettigan, J. P., Schnell, M. J., & Dietzschold, B. (2002). Overexpression of the rabies virus glycoprotein results in enhancement of apoptosis and antiviral immune response. [Comparative Study Research Support, U.S. Gov't, P.H.S.]. J Virol, 76(7), 3374-3381.

Fekadu, M., Chandler, F. W., & Harrison, A. K. (1982). Pathogenesis of rabies in dogs inoculated with an Ethiopian rabies virus strain. Immunofluorescence, histologic and ultrastructural studies of the central nervous system. [Research Support, Non-U.S. Gov't]. Arch Virol, 71(2), 109-126.

Fenstermacher, J., Gross, P., Sposito, N., Acuff, V., Pettersen, S., & Gruber, K. (1988). Structural and functional variations in capillary systems within the brain. [Research Support, U.S. Gov't, P.H.S.]. Ann N Y Acad Sci, 529, 21-30.

Glass, W. G., Rosenberg, H. F., & Murphy, P. M. (2003). Chemokine regulation of inflammation during acute viral infection. [Review]. Curr Opin Allergy Clin Immunol, 3(6), 467-473. doi: 10.1097/01.all.0000104448.09202.91
Gloor, S. M., Wachtel, M., Bolliger, M. F., Ishihara, H., Landmann, R., & Frei, K. (2001). Molecular and cellular permeability control at the blood-brain barrier. [Research Support, Non-U.S. Gov't Review]. Brain Res Brain Res Rev, 36(2-3), 258-264.

Greenwood, J., Heasman, S. J., Alvarez, J. I., Prat, A., Lyck, R., & Engelhardt, B. (2011). Review: leucocyte-endothelial cell crosstalk at the blood-brain barrier: a prerequisite for successful immune cell entry to the brain. [Review]. Neuropathol Appl Neurobiol, 37(1), 24-39. doi: 10.1111/j.1365-2990.2010.01140.x

Hooper, D. C., Morimoto, K., Bette, M., Weihe, E., Koprowski, H., & Dietzschold, B. (1998). Collaboration of antibody and inflammation in clearance of rabies virus from the central nervous system. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.]. J Virol, 72(5), 3711-3719.

Hooper, D. C., Phares, T. W., Fabis, M. J., & Roy, A. (2009). The production of antibody by invading B cells is required for the clearance of rabies virus from the central nervous system. [Research Support, N.I.H., Extramural]. PLoS Negl Trop Dis, 3(10), e535. doi: 10.1371/journal.pntd.0000535

Hooper, D. C., Roy, A., Barkhouse, D. A., Li, J., & Kean, R. B. (2011). Rabies virus clearance from the central nervous system. [Research Support, N.I.H., Extramural Review]. Adv Virus Res, 79, 55-71. doi: 10.1016/B978-0-12-387040-7.00004-4

Hooper, D. C., Roy, A., Kean, R. B., Phares, T. W., & Barkhouse, D. A. (2011). Therapeutic immune clearance of rabies virus from the CNS. Future Virol, 6(3), 387-397. doi: 10.2217/fvl.10.88

Huang, C. T., Li, Z., Huang, Y., Zhang, G., Zhou, M., Chai, Q., . . . Fu, Z. F. (2014). Enhancement of blood-brain barrier permeability is required for intravenously administered virus neutralizing antibodies to clear an established rabies virus infection from the brain and prevent the development of rabies in mice. [Research Support, N.I.H., Extramural]. Antiviral Res, 110, 132-141. doi: 10.1016/j.antiviral.2014.07.013

Human rabies--Minnesota, 2007. (2008). [Case Reports]. MMWR Morb Mortal Wkly Rep, 57(17), 460-462.

Human rabies--Mississippi, 2005. (2006). [Case Reports]. MMWR Morb Mortal Wkly Rep, 55(8), 207-208.

Hwang, E. S., Szabo, S. J., Schwartzberg, P. L., & Glimcher, L. H. (2005). T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.]. Science, 307(5708), 430-433. doi: 10.1126/science.1103336

Iadecola, C. (2004). Neurovascular regulation in the normal brain and in Alzheimer's disease. [Research Support, U.S. Gov't, P.H.S. Review]. Nat Rev Neurosci, 5(5), 347-360. doi: 10.1038/nrn1387

Jackson, A. C., Randle, E., Lawrance, G., & Rossiter, J. P. (2008). Neuronal apoptosis does not play an important role in human rabies encephalitis. [Research Support, Non-U.S. Gov't]. J Neurovirol, 14(5), 368-375. doi: 10.1080/13550280802216502

Jackson, A. C., Rasalingam, P., & Weli, S. C. (2006). Comparative pathogenesis of recombinant rabies vaccine strain SAD-L16 and SAD-D29 with replacement of Arg333 in the glycoprotein after peripheral inoculation of neonatal mice: less neurovirulent strain is a stronger inducer of neuronal apoptosis. [Comparative Study Research Support, Non-U.S. Gov't]. Acta Neuropathol, 111(4), 372-378. doi: 10.1007/s00401-005-0006-z

Johnson, N., Cunningham, A. F., & Fooks, A. R. (2010). The immune response to rabies virus infection and vaccination. [Research Support, Non-U.S. Gov't Review]. Vaccine, 28(23), 3896-3901. doi: 10.1016/j.vaccine.2010.03.039

Lawrence, T., Willoughby, D. A., & Gilroy, D. W. (2002). Anti-inflammatory lipid mediators and insights into the resolution of inflammation. [Research Support, Non-U.S. Gov't Review]. Nat Rev Immunol, 2(10), 787-795. doi: 10.1038/nri915

Lebrun, A., Portocarrero, C., Kean, R. B., Barkhouse, D. A., Faber, M., & Hooper, D. C. (2015). T-bet Is Required for the Rapid Clearance of Attenuated Rabies Virus from Central Nervous System Tissue. J Immunol. doi: 10.4049/jimmunol.1501274

Liao, P. H., Yang, H. H., Chou, P. T., Wang, M. H., Chu, P. C., Liu, H. L., & Chen, L. K. (2012). Sufficient virus-neutralizing antibody in the central nerve system improves the survival of rabid rats. [Research Support, Non-U.S. Gov't]. J Biomed Sci, 19, 61. doi: 10.1186/1423-0127-19-61

Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., . . . Kipnis, J. (2015). Structural and functional features of central nervous system lymphatic vessels. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]. Nature, 523(7560), 337-341. doi: 10.1038/nature14432

Masatani, T., Ito, N., Shimizu, K., Ito, Y., Nakagawa, K., Sawaki, Y., . . . Sugiyama, M. (2010). Rabies virus nucleoprotein functions to evade activation of the RIG-I-mediated antiviral response. [Research Support, Non-U.S. Gov't]. J Virol, 84(8), 4002-4012. doi: 10.1128/JVI.02220-09

Matyszak, M. K., & Perry, V. H. (1996). The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. [Research Support, Non-U.S. Gov't]. Neuroscience, 74(2), 599-608.
Maurya, I., Vagholkar, K., Patel, B., Siddiqui, M., Tiwari, S., & Maurya, P. (2015). State of globe: rabies: the lethality since antiquity! J Glob Infect Dis, 7(1), 1-2. doi: 10.4103/0974-777X.150880

Medawar, P. B. (1948). Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol, 29(1), 58-69.

Morimoto, K., Hooper, D. C., Carbaugh, H., Fu, Z. F., Koprowski, H., & Dietzschold, B. (1998). Rabies virus quasispecies: implications for pathogenesis. [Comparative Study]. Proc Natl Acad Sci U S A, 95(6), 3152-3156.
Morimoto, K., Hooper, D. C., 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. [Research Support, U.S. Gov't, P.H.S.]. J Virol, 73(1), 510-518.

Morimoto, K., McGettigan, J. P., Foley, H. D., Hooper, D. C., Dietzschold, B., & Schnell, M. J. (2001). Genetic engineering of live rabies vaccines. [Research Support, U.S. Gov't, P.H.S.]. Vaccine, 19(25-26), 3543-3551.
Murphy, F. A. (1977). Rabies pathogenesis. Arch Virol, 54(4), 279-297.

O'Shea, J. J., & Paul, W. E. (2010). Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. [Research Support, N.I.H., Intramural Review]. Science, 327(5969), 1098-1102. doi: 10.1126/science.1178334

Oestreich, K. J., Huang, A. C., & Weinmann, A. S. (2011). The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]. J Exp Med, 208(5), 1001-1013. doi: 10.1084/jem.20102144

Oldendorf, W. H., Cornford, M. E., & Brown, W. J. (1977). The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. [Comparative Study Research Support, U.S. Gov't, P.H.S.]. Ann Neurol, 1(5), 409-417. doi: 10.1002/ana.410010502

Perry, V. H. (1998). A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation. [Research Support, Non-U.S. Gov't Review]. J Neuroimmunol, 90(2), 113-121.

Pfefferkorn, C., Kallfass, C., Lienenklaus, S., Spanier, J., Kalinke, U., Rieder, M., . . . Staeheli, P. (2016). Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain. [Research Support, Non-U.S. Gov't]. J Virol, 90(4), 2031-2038. doi: 10.1128/JVI.02979-15

Phares, T. W., Fabis, M. J., Brimer, C. M., Kean, R. B., & Hooper, D. C. (2007). A peroxynitrite-dependent pathway is responsible for blood-brain barrier permeability changes during a central nervous system inflammatory response: TNF-alpha is neither necessary nor sufficient. [Comparative Study Research Support, N.I.H., Extramural]. J Immunol, 178(11), 7334-7343.

Phares, T. W., Kean, R. B., Mikheeva, T., & Hooper, D. C. (2006). Regional differences in blood-brain barrier permeability changes and inflammation in the apathogenic clearance of virus from the central nervous system. [Comparative Study Research Support, N.I.H., Extramural]. J Immunol, 176(12), 7666-7675.

Prosniak, M., Hooper, D. C., Dietzschold, B., & Koprowski, H. (2001). Effect of rabies virus infection on gene expression in mouse brain. [Research Support, U.S. Gov't, P.H.S.]. Proc Natl Acad Sci U S A, 98(5), 2758-2763. doi: 10.1073/pnas.051630298

Prosniak, M., Zborek, A., Scott, G. S., Roy, A., Phares, T. W., Koprowski, H., & Hooper, D. C. (2003). Differential expression of growth factors at the cellular level in virus-infected brain. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.]. Proc Natl Acad Sci U S A, 100(11), 6765-6770. doi: 10.1073/pnas.0430999100
Rabies vaccines: WHO position paper--recommendations. (2010). Vaccine, 28(44), 7140-7142. doi: 10.1016/j.vaccine.2010.08.082

Ransohoff, R. M., & Engelhardt, B. (2012). The anatomical and cellular basis of immune surveillance in the central nervous system. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review]. Nat Rev Immunol, 12(9), 623-635. doi: 10.1038/nri3265

Ray, N. B., Power, C., Lynch, W. P., Ewalt, L. C., & Lodmell, D. L. (1997). Rabies viruses infect primary cultures of murine, feline, and human microglia and astrocytes. Arch Virol, 142(5), 1011-1019.

Recovery of a patient from clinical rabies--California, 2011. (2012). [Case Reports Research Support, U.S. Gov't, P.H.S.]. MMWR Morb Mortal Wkly Rep, 61(4), 61-65.

Recovery of a patient from clinical rabies--Wisconsin, 2004. (2004). [Case Reports]. MMWR Morb Mortal Wkly Rep, 53(50), 1171-1173.

Reid, J. E., & Jackson, A. C. (2001). Experimental rabies virus infection in Artibeus jamaicensis bats with CVS-24 variants. [Research Support, Non-U.S. Gov't]. J Neurovirol, 7(6), 511-517. doi: 10.1080/135502801753248097

Rieder, M., Brzozka, K., Pfaller, C. K., Cox, J. H., Stitz, L., & Conzelmann, K. K. (2011). Genetic dissection of interferon-antagonistic functions of rabies virus phosphoprotein: inhibition of interferon regulatory factor 3 activation is important for pathogenicity. [Research Support, Non-U.S. Gov't]. J Virol, 85(2), 842-852. doi: 10.1128/JVI.01427-10

Roy, A., & Hooper, D. C. (2007). Lethal silver-haired bat rabies virus infection can be prevented by opening the blood-brain barrier. [Research Support, N.I.H., Extramural]. J Virol, 81(15), 7993-7998. doi: 10.1128/JVI.00710-07

Roy, A., & Hooper, D. C. (2008). Immune evasion by rabies viruses through the maintenance of blood-brain barrier integrity. [Research Support, N.I.H., Extramural]. J Neurovirol, 14(5), 401-411. doi: 10.1080/13550280802235924

Roy, A., Phares, T. W., Koprowski, H., & Hooper, D. C. (2007). Failure to open the blood-brain barrier and deliver immune effectors to central nervous system tissues leads to the lethal outcome of silver-haired bat rabies virus infection. [Research Support, N.I.H., Extramural]. J Virol, 81(3), 1110-1118. doi: 10.1128/JVI.01964-06

Rubin, L. L., & Staddon, J. M. (1999). The cell biology of the blood-brain barrier. [Review]. Annu Rev Neurosci, 22, 11-28. doi: 10.1146/annurev.neuro.22.1.11
Rupprecht, C. E. (1996). Rhabdoviruses: Rabies Virus. In S. Baron (Ed.), Medical Microbiology (4th ed.). Galveston (TX).

Sarmento, L., Li, X. Q., Howerth, E., Jackson, A. C., & Fu, Z. F. (2005). Glycoprotein-mediated induction of apoptosis limits the spread of attenuated rabies viruses in the central nervous system of mice. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]. J Neurovirol, 11(6), 571-581. doi: 10.1080/13550280500385310

Schnell, M. J., Mebatsion, T., & Conzelmann, K. K. (1994). Infectious rabies viruses from cloned cDNA. [Research Support, Non-U.S. Gov't]. EMBO J, 13(18), 4195-4203.

Scott, C. A., Rossiter, J. P., Andrew, R. D., & Jackson, A. C. (2008). Structural abnormalities in neurons are sufficient to explain the clinical disease and fatal outcome of experimental rabies in yellow fluorescent protein-expressing transgenic mice. [Research Support, Non-U.S. Gov't]. J Virol, 82(1), 513-521. doi: 10.1128/JVI.01677-07

Sedlakova, R., Shivers, R. R., & Del Maestro, R. F. (1999). Ultrastructure of the blood-brain barrier in the rabbit. [Research Support, Non-U.S. Gov't]. J Submicrosc Cytol Pathol, 31(1), 149-161.

Shinkai, Y., Rathbun, G., Lam, K. P., Oltz, E. M., Stewart, V., Mendelsohn, M., . . . et al. (1992). RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.]. Cell, 68(5), 855-867.

Suja, M. S., Mahadevan, A., Madhusudhana, S. N., Vijayasarathi, S. K., & Shankar, S. K. (2009). Neuroanatomical mapping of rabies nucleocapsid viral antigen distribution and apoptosis in pathogenesis in street dog rabies--an immunohistochemical study. [Research Support, Non-U.S. Gov't]. Clin Neuropathol, 28(2), 113-124.

Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.]. Cell, 100(6), 655-669.

Terry, R. L., Getts, D. R., Deffrasnes, C., van Vreden, C., Campbell, I. L., & King, N. J. (2012). Inflammatory monocytes and the pathogenesis of viral encephalitis. [Research Support, Non-U.S. Gov't Review]. J Neuroinflammation, 9, 270. doi: 10.1186/1742-2094-9-270

Tsiang, H. (1979). Evidence for an intraaxonal transport of fixed and street rabies virus. J Neuropathol Exp Neurol, 38(3), 286-299.

Tsiang, H., Koulakoff, A., Bizzini, B., & Berwald-Netter, Y. (1983). Neurotropism of rabies virus. An in vitro study. [Research Support, Non-U.S. Gov't]. J Neuropathol Exp Neurol, 42(4), 439-452.

Wang, H., Zhang, G., Wen, Y., Yang, S., Xia, X., & Fu, Z. F. (2011). Intracerebral administration of recombinant rabies virus expressing GM-CSF prevents the development of rabies after infection with street virus. [Research Support, N.I.H., Extramural]. PLoS One, 6(9), e25414. doi: 10.1371/journal.pone.0025414

Wang, Z. W., Sarmento, L., Wang, Y., Li, X. Q., Dhingra, V., Tseggai, T., . . . Fu, Z. F. (2005). Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. [Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.]. J Virol, 79(19), 12554-12565. doi: 10.1128/JVI.79.19.12554-12565.2005

WHO Expert Consultation on rabies. (2005). World Health Organ Tech Rep Ser, 931, 1-88, back cover.

WHO Expert Consultation on Rabies. Second report. (2013). [Research Support, Non-U.S. Gov't]. World Health Organ Tech Rep Ser(982), 1-139, back cover.

Willoughby, R. E., Jr., Tieves, K. S., Hoffman, G. M., Ghanayem, N. S., Amlie-Lefond, C. M., Schwabe, M. J., . . . Rupprecht, C. E. (2005). Survival after treatment of rabies with induction of coma. [Case Reports]. N Engl J Med, 352(24), 2508-2514. doi: 10.1056/NEJMoa050382

Wolburg, H., & Lippoldt, A. (2002). Tight junctions of the blood-brain barrier: development, composition and regulation. [Review]. Vascul Pharmacol, 38(6), 323-337.

Yamada, S., DePasquale, M., Patlak, C. S., & Cserr, H. F. (1991). Albumin outflow into deep cervical lymph from different regions of rabbit brain. [Comparative Study Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.]. Am J Physiol, 261(4 Pt 2), H1197-1204.

Yan, X., Prosniak, M., Curtis, M. T., Weiss, M. L., Faber, M., Dietzschold, B., & Fu, Z. F. (2001). Silver-haired bat rabies virus variant does not induce apoptosis in the brain of experimentally infected mice. [Research Support, U.S. Gov't, P.H.S.]. J Neurovirol, 7(6), 518-527. doi: 10.1080/135502801753248105

Zlokovic, B. V. (2008). The blood-brain barrier in health and chronic neurodegenerative disorders. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review]. Neuron, 57(2), 178-201. doi: 10.1016/j.neuron.2008.01.003