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Title: Examination of the host response in brain tissue during herpes simplex virus encephalitis
Author: Ismail, Zarini
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2013
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Background: Herpes simplex virus encephalitis (HSVE) continues to be one of the most devastating infections of the central nervous system (CNS) despite effective antiviral treatment. The pathogenesis of the disease has not been completely studied, and little is known about the molecular mechanisms underlying cellular death and tissue damage. Better understanding of the HSVE pathogenesis is required to develop better treatment and reduce of patients’ morbidity and mortality. Method: Post-mortem brain tissue from adult HSVE (n=3) and road traffic accident (RTA; n=5) cases were examined to characterise the neuropathological changes, immune activation and infiltration of the inflammatory cells, and changes in transcript abundance during herpes simplex virus type 1 (HSV-1) infection. Patients with HIV encephalitis (n=3) provided further control tissue. Results: There was extensive neuropathological change and widespread necrosis in temporal and frontal regions of the brain among the HSVE cases. CNS cells showed characteristic signs of lytic damage. Infection was associated with microglial activation and infiltration by macrophages and lymphocytes. Genome-wide gene-expression micro-array analysis of the brain tissue demonstrated 287 host transcripts with significantly lower abundance in HSVE compared to RTA cases. Mitochondrial DNA encoded transcripts were significantly over-represented in the set of low abundant transcripts (p<0.0001), with 28 out of 33 mitochondrial genes represented on the array exhibiting lower abundance. Reflecting the array findings, immune staining for cytochrome c oxidase subunit 1, a mitochondrial encoded protein, was reduced in HSVE compared to RTA cases. Furthermore, there was a reciprocal pattern of staining among the HSVE patients, with reduced staining for cytochrome c oxidase subunit 1 in areas of high HSV1 staining. Conclusion: The neuropathological findings confirm previous findings for HSVE. However, the transcript data demonstrates a new finding. There is a preferential loss of mitochondrial transcripts in brain tissue of HSVE patients. The immuno-histochemical results support the array findings. The tissue results also imply that the mitochondrial damage occurs in response to HSV infection. The findings suggest that adjunctive treatments which preserve mitochondrial function could be developed as a new therapeutic option in the treatment of HSVE.
Supervisor: Griffiths, Michael Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available