Use this URL to cite or link to this record in EThOS:
Title: Neuropathogenesis of Japanese encephalitis in a rhesus monkey challenge model
Author: Myint, Khin Saw
ISNI:       0000 0004 2734 708X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
Availability of Full Text:
Access from EThOS:
Access from Institution:
Japanese encephalitis (JE) is a major cause of childhood mortality and morbidity in Asia and for which there is no treatment. In addition to direct viral cytopathology, a poorly regulated inflammatory response is postulated to contribute to the pathogenesis, possibly through bystander death of uninfected neurons; but there have been few studies examining this. We used a validated macaque model of JE to characterize the inflammatory response and cytopathic effects of JE virus (JEV) in the brain. There was strong perivascular infiltration of leukocytes, particularly T cells, with endothelial cell activation, vascular damage and leakage of serum across the blood brain barrier (888). Adjacent parenchyma exhibited macrophage rich infiltrates, with astrocyte and microglia activation. JEV antigen was seen mostly in neurons, but there was no correlation between intensity of viral infection and degree of inflammatory response. Apoptotic cell death was seen in both infected and non-infected neurons. Interferon (IFN)-a, which is a microglial activator, was also expressed by both. Tumour necrosis factor-a (which can induce neuronal apoptosis), inducible nitric oxide synthase and nitrotyrosine (involved in nitric oxide production) was expressed by microglial cells, astrocytes and to some extent macrophages. The same cells expressed matrix metalloproteinase (MMP)-2 whilst MMP-9 was expressed by neurons; both MMPs cause BBB disruption. The results are consistent with JEV inducing neuronal apoptotic death and release of cytokines such as IFN-a; these are postulated to initiate microglial activation, and release of pro-inflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected bystander neurons. Activation of astrocytes, microglial and endothelial cells likely contributes to inflammatory cell recruitment and BBB breakdown. These results provide strong evidence that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogensis of JE, and suggest new paths for targeted therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral