Abstract
Smallpox vaccination might be associated with adverse reactions, ranging in severity from benign to lethal. One of the most serious complications is postvaccinal encephalitis. The aim of this study was to identify early markers for vaccinia virus (VACV) induced encephalitis. For this purpose we infected mice intracranially with VACV-Lister or VACV-WR. Histopathological analysis showed that following infection with VACV-WR tissue damage in the brain spatially and temporally correlated with virus replication, infiltration of white blood cells and apoptosis. None of the above markers was observed upon infection with the vaccine strain Lister.
MMP-9 is a serum factor known for its correlation to BBB integrity and encephalitis in humans. We found that in sera of VACV-Lister infected animals, MMP-9 levels did not change throughout the infection. However, during VACV-WR infection, in the first 2 days levels of MMP-9 were significantly low than the controls and subsequently rose to levels which were significantly higher than the controls. Elevated MMP-9 was associated with damage to the brain and to BBB integrity.
In conclusion, efficient virus replication in the brain causes significant brain damage followed by BBB brake-down and release of MMP-9 to the serum, markers which were not observed when the attenuated strain was examined. Thus, we suggest MMP-9 as a possible non-invasive serum indicator for encephalitis caused by VACV virus.
Equal contribution by Tomer Israely and Sharon Melamed.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bever, C. T., Jr. & Rosenberg, G. A. (1999) Matrix metalloproteinases in multiple sclerosis: targets of therapy or markers of injury? Neurology, 53, 1380–1.
Birkedal-Hansen, H. (1993) Role of matrix metalloproteinases in human periodontal diseases. J Periodontol, 64, 474–84.
Bonoiu, A., Mahajan, S. D., Ye, L., Kumar, R., Ding, H., Yong, K. T., Roy, I., Aalinkeel, R., Nair, B., Reynolds, J. L., Sykes, D. E., Imperiale, M. A., Bergey, E. J., Schwartz, S. A. & Prasad, P. N. (2009) MMP-9 gene silencing by a quantum dot-siRNA nanoplex delivery to maintain the integrity of the blood brain barrier. Brain Res, 1282, 142–55.
Booss, J. & Davis, L. E. (2003) Smallpox and smallpox vaccination: neurological implications. Neurology, 60, 1241–5.
Boz, C., Ozmenoglu, M., Velioglu, S., Kilinc, K., Orem, A., Alioglu, Z. & Altunayoglu, V. (2006) Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in patients with relapsing-remitting multiple sclerosis treated with interferon beta. Clin Neurol Neurosurg, 108, 124–8.
Canete Soler, R., Gui, Y. H., Linask, K. K. & Muschel, R. J. (1995) MMP-9 (gelatinase B) mRNA is expressed during mouse neurogenesis and may be associated with vascularization. Brain Res Dev Brain Res, 88, 37–52.
Casey, C. G., Iskander, J. K., Roper, M. H., Mast, E. E., Wen, X. J., Torok, T. J., Chapman, L. E., Swerdlow, D. L., Morgan, J., Heffelfinger, J. D., Vitek, C., Reef, S. E., Hasbrouck, L. M., Damon, I., Neff, L., Vellozzi, C., Mccauley, M., Strikas, R. A. & Mootrey, G. (2005) Adverse events associated with smallpox vaccination in the United States, January-October 2003. Jama, 294, 2734–43.
CDC (2004) Centers for Disease Control and Prevention (CDC). Update: adverse events following civilian smallpox vaccination-United States, 2003. Morb Mortal Wkly Rep, 53, 106–7.
Chen, K. M., Lee, H. H., Chou, H. L., Liu, J. Y., Tsai, B. C. & Lai, S. C. (2005) Upregulation of MMP-9/TIMP-1 enzymatic system in eosinophilic meningitis caused by Angiostrongylus cantonensis. Int J Exp Pathol, 86, 81–9.
Del Bigio, M. R. & Jacque, C. M. (1995) Localization of proteinase expression in the developing rabbit brain. Brain Res Dev Brain Res, 86, 345–7.
Fenner, F., Henderson, D. A., Arita, I., Jezek, Z. & Ladnyi, I. D. (1988) Smallpox and its Eradication. World Health Organization, Geneva, Switzerland.
Henderson, D. A. & Moss, B. (1999) Smallpox and vaccinia. In Plotkin, S. A. & Orenstein, W. A. (eds.), Vaccines, W.B Saunders Company, Philadelphia, PA.
Ichiyama, T., Kajimoto, M., Suenaga, N., Maeba, S., Matsubara, T. & Furukawa, S. (2006) Serum levels of matrix metalloproteinase-9 and its tissue inhibitor (TIMP-1) in acute disseminated encephalomyelitis. J Neuroimmunol, 172, 182–6.
Ichiyama, T., Morishima, T., Kajimoto, M., Matsushige, T., Matsubara, T. & Furukawa, S. (2007a) Matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in influenza-associated encephalopathy. Pediatr Infect Dis J, 26, 542–4.
Ichiyama, T., Siba, P., Suarkia, D., Takasu, T., Miki, K., Kira, R., Kusuhara, K., Hara, T., Toyama, J. & Furukawa, S. (2007b) Serum levels of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in subacute sclerosing panencephalitis. J Neurol Sci, 252, 45–8.
Keogh, B., Sheahan, B. J., Atkins, G. J. & Mills, K. H. (2003) Inhibition of matrix metalloproteinases ameliorates blood-brain barrier disruption and neuropathological lesions caused by avirulent Semliki Forest virus infection. Vet Immunol Immunopathol, 94, 185–90.
Lane, J. M., Ruben, F. L., Abrutyn, E. & Millar, J. D. (1970) Deaths attributable to smallpox vaccination, 1959 to 1966, and 1968. Jama, 212, 441–4.
Martinez-Torres, F. J., Wagner, S., Haas, J., Kehm, R., Sellner, J., Hacke, W., Meyding-Lamade, U. (2004) Increased presence of matrix metalloproteinases 2 and 9 in short- and long-term experimental herpes simplex virus encephalitis, Neuroscience letters, 368, 274–278.
Mishra, M. K., Dutta, K., Saheb, S. K. & Basu, A. (2009) Understanding the molecular mechanism of blood-brain barrier damage in an experimental model of Japanese encephalitis: correlation with minocycline administration as a therapeutic agent. Neurochem Int, 55, 717–23.
Overall, C. M. & Lopez-Otin, C. (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer, 2, 657–72.
Romanic, A. M. & Madri, J. A. (1994) Extracellular matrix-degrading proteinases in the nervous system. Brain Pathol, 4, 145–56.
Rosenberg, G. A., Dencoff, J. E., Mcguire, P. G., Liotta, L. A. & Stetler-Stevenson, W. G. (1994) Injury-induced 92-kilodalton gelatinase and urokinase expression in rat brain. Lab Invest, 71, 417–22.
Scott, T. F. (1967) Postinfectious and vaccinal encephalitis. Med Clin North Am, 51, 701–17.
Sejvar, J. J., Labutta, R. J., Chapman, L. E., Grabenstein, J. D., Iskander, J. & Lane, J. M. (2005) Neurologic adverse events associated with smallpox vaccination in the United States, 2002–2004. Jama, 294, 2744–50.
Suenaga, N., Ichiyama, T., Kubota, M., Isumi, H., Tohyama, J. & Furukawa, S. (2008) Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures. J Neurol Sci, 266, 126–30.
Svedin, P., Hagberg, H., Savman, K., Zhu, C. & Mallard, C. (2007) Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neurosci, 27, 1511–8.
Wang, P., Dai, J., Bai, F., Kong, K. F., Wong, S. J., Montgomery, R. R., Madri, J. A. & Fikrig, E. (2008) Matrix metalloproteinase 9 facilitates West Nile virus entry into the brain. J Virol, 82, 8978–85.
Waubant, E., Goodkin, D. E., Gee, L., Bacchetti, P., Sloan, R., Stewart, T., Andersson, P. B., Stabler, G. & Miller, K. (1999) Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology, 53, 1397–401.
WHO (1980) World Health Organization. The global eradication of smallpox: final report of the global commission for the certification of smallpox eradication. History of International Public Health No. 4. World Health Organization, Geneva.
Yong, V. W., Zabad, R. K., Agrawal, S., Goncalves Dasilva, A. & Metz, L. M. (2007) Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci, 259, 79–84.
Acknowledgments
We wish to thank Dr. Shira Chapman, Dr. Tamar Kadar and Dr. Trevor Waner for their valuable contribution to this study.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media B.V.
About this paper
Cite this paper
Israely, T. et al. (2010). MMP-9 as a Marker for Vaccinia Virus Related Encephalitis. In: Shafferman, A., Ordentlich, A., Velan, B. (eds) The Challenge of Highly Pathogenic Microorganisms. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9054-6_15
Download citation
DOI: https://doi.org/10.1007/978-90-481-9054-6_15
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-90-481-9053-9
Online ISBN: 978-90-481-9054-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)