Examining the impact of anti-inflammatory and anti-viral treatments in human brain cell infection models for Herpes Simplex virus encephalitis

Segura, JV (2018) Examining the impact of anti-inflammatory and anti-viral treatments in human brain cell infection models for Herpes Simplex virus encephalitis. PhD thesis, University of Liverpool.

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Abstract

Herpes Simplex Encephalitis (HSE) is a lethal brain inflammation induced by Herpes Simplex virus (HSV), mainly HSV-1 subtype. Brain damage associated with HSE is reported to be caused directly by the virus and indirectly by the host immune responses. Aciclovir, the gold standard anti-viral therapy, targets HSV replication but not brain inflammation. Hence, administration of anti-inflammatory drugs alongside aciclovir may improve outcome in HSE patients. However, clinicians worry that immune-modulating drugs may enhance HSV replication during acute HSE. A few small clinical studies have demonstrated that administering glucocorticoids in combination with aciclovir improve patient outcome. However, change in HSV viral load was not examined. Interestingly, tumor necrosis factor alpha (TNF-α), a known pro-inflammatory mediator, exhibits high levels in cerebrospinal fluid among HSE patients. To date, there are no studies examining anti-TNF therapy in HSE patients or human models. Further studies need to be performed to investigate the effect of anti-TNF agents and glucocorticoids on human brain cell survival and HSV viral load, to support future clinical studies. In my thesis, I have studied the impact of dexamethasone (a glucorticoid) and infliximab (an anti-TNF agent) in acute (up to 72 hours post-infection) HSV-1-infected human brain cell models. My study shows dexamethasone and infliximab administered in combination with aciclovir were not detrimental to cell viability or cell activity (as measured by mitochondrial activity) among HSV-1-infected neuroblastoma or microglia. I also showed these drugs do not enhance HSV-1 replication in these cells. Interestingly, Infliximab (in a single dose) was protective against HSV-1 infection in neuroblastoma and microglia cells. It led to a rapid reduction of HSV DNA abundance in the culture medium of the infected cells and slowed reduction in live cell number and activity. Nonetheless, neither dexamethasone nor infliximab showed a significant benefit in combination with aciclovir compared to aciclovir alone. I have also developed co-culture models of HSE using primary astrocytes or neuroblastoma cells co-cultured with microglial cells to begin to enable evaluation of drug therapies in more complex models. My results highlight that adjunctive anti-inflammatory therapies do not enhance HSV replication during acute infection of human brain cells. My findings also suggest infliximab may have potential, in different dose regimens, as a future adjunctive therapy in HSE.

Item Type:	Thesis (PhD)
Divisions:	Faculty of Health and Life Sciences
Depositing User:	Symplectic Admin
Date Deposited:	26 Mar 2019 12:24
Last Modified:	19 Jan 2023 01:04
DOI:	10.17638/03032468
Supervisors:	Griffiths, Michael Solomon, Tom ORCID: 0000-0001-7266-6547
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3032468