Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation.
Cerebrovascular complications including cerebral edema, raised intracranial pressure and hemorrhage contribute to the high mortality and morbidity of herpes-simplex virus encephalitis (HSE). We examined changes of collagen type IV, the major constituent of the neurovascular matrix, together with expression and localization of matrix-degrading enzymes during the development of acute HSE. In an experimental model of focal HSE, we found that early, symptomatic HSE (3 days after infection) and acute, fully developed HSE (7 days after infection) are associated with significantly raised levels of matrix-metalloproteinase-9 (MMP-9) (both P<0.05). In situ zymography of brain sections revealed that the increase of MMP-9 was restricted to the cerebral vasculature in early HSE and further expanded towards the perivascular space and adjacent tissue in acute HSE. Around the cerebral vasculature, we observed that MMP-9 activity was insufficiently counterbalanced by its endogenous tissue inhibitor of MMP (TIMP) TIMP-1, resulting in loss of collagen type IV. Our findings suggest that MMP-9 is involved in the evolution of HSE by causing damage to the cerebral vasculature. The degradation of the neurovascular matrix in HSE facilitates the development of cerebrovascular complications and may represent a target for novel adjuvant treatment strategies.
Sellner
Johann
J
Department of Neurology, University Hospital Bern, Inselspital, Freiburgstrasse, CH-3010 Bern, Switzerland.
Simon
Franziska
F
Meyding-Lamade
Uta
U
Leib
Stephen L
SL
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D020803:Encephalitis, Herpes Simplex / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D013997:Time Factors; D019562:Viral Load
D024141:Collagen Type IV; D020778:Matrix Metalloproteinase 2