Mechanisms of primary axonal damage in a viral model of multiple sclerosis.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Recent studies have demonstrated that significant axonal injury also occurs in MS patients and correlates with neurological dysfunction, but it is not known whether this neuronal damage is a primary disease process, or occurs only secondary to demyelination. In the current studies, neurotropic strains of mouse hepatitis virus (MHV) that induce meningitis, encephalitis, and demyelination in the CNS, an animal model of MS, were used to evaluate mechanisms of axonal injury. The pathogenic properties of genetically engineered isogenic spike protein recombinant demyelinating and nondemyelinating strains of MHV were compared. Studies demonstrate that a demyelinating strain of MHV causes concomitant axonal loss and macrophage-mediated demyelination. The mechanism of axonal loss and demyelination in MHV infection is dependent on successful transport of virus from gray matter to white matter using the MHV host attachment spike glycoprotein. Our data show that axonal loss and demyelination can be independent direct viral cytopathic events, and suggest that similar direct axonal damage may occur in MS. These results have important implications for the design of neuroprotective strategies for CNS demyelinating disease, and our model identifies the spike protein as a therapeutic target to prevent axonal transport of neurotropic viruses.
Das Sarma
Jayasri
J
Department of Neurology and Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. dassarmaj@iiserkol.ac.in
Kenyon
Lawrence C
LC
Hingley
Susan T
ST
Shindler
Kenneth S
KS
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D006517:Murine hepatitis virus / Q000235:genetics / Q000472:pathogenicity; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000821:virology
D018836:Inflammation Mediators
Virology. 2001 Jan 20;279(2):371-4
11162792
N Engl J Med. 1998 Jan 29;338(5):278-85
9445407
J Gen Virol. 1988 Dec;69 ( Pt 12):2939-52
3058868
Mult Scler. 2001 Aug;7(4):221-6
11548980
J Virol. 1994 Sep;68(9):5403-10
7520090
Curr Opin Neurol. 2001 Jun;14(3):259-69
11371747
J Virol. 2001 Jul;75(13):6115-20
11390613
J Virol. 2008 Jun;82(11):5519-26
18385249
Microbes Infect. 2001 May;3(6):475-9
11377209
J Virol. 1997 Feb;71(2):1688-91
8995701
Virology. 1998 May 10;244(2):483-94
9601516
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4659-63
9114047
Brain. 1997 Mar;120 ( Pt 3):393-9
9126051
J Neuropathol Exp Neurol. 1997 Nov;56(11):1262-8
9370237
J Virol. 2003 Jan;77(2):830-40
12502799
Nat Rev Neurosci. 2002 Apr;3(4):291-301
11967559
J Virol. 2008 Sep;82(17):8882-6
18579591
Epidemiology. 2001 May;12(3):301-6
11337603
Curr Opin Neurol. 1999 Jun;12(3):295-302
10499174
Virology. 1992 Nov;191(1):517-22
1413526
Brain. 2000 Feb;123 ( Pt 2):308-17
10648438
J Neurol Sci. 1984 Jan;63(1):63-74
6321668
J Virol. 1994 May;68(5):2915-28
8151762
EMBO J. 2002 May 1;21(9):2076-86
11980704
Neurobiol Aging. 2006 Feb;27(2):293-305
16002188
Brain Res Bull. 1996;41(6):327-33
8973836
J Neurovirol. 2002 Oct;8(5):381-91
12402164
Neurology. 2001 Oct 9;57(7):1248-52
11591844
Am J Pathol. 2000 Jul;157(1):267-76
10880396
J Virol. 2002 Dec;76(23):11819-26
12414924
J Neurol Sci. 1990 Apr;96(1):103-23
2351985
Neurology. 1984 May;34(5):597-603
6324031
Am J Pathol. 2003 Apr;162(4):1259-69
12651618
Virology. 1997 Jan 6;227(1):215-9
9007076
J Virol. 2001 Mar;75(5):2452-7
11160748
Acta Neuropathol. 1997 Feb;93(2):184-9
9039467
J Virol. 1985 Dec;56(3):912-20
2999444
J Virol. 2000 Oct;74(19):9206-13
10982367
Springer Semin Immunopathol. 2002;24(2):105-25
12503060
J Virol. 1993 Jan;67(1):1-8
8380065