Identification and characterisation of host factors essential for Human Cytomegalovirus Infection

Amratia, Pragati 2022. Identification and characterisation of host factors essential for Human Cytomegalovirus Infection. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Human cytomegalovirus (HCMV) is a widespread β-herpesvirus that establishes lifelong infection in hosts. Although the infection is typically asymptomatic in healthy individuals, it causes significant morbidity and mortality in the immunocompromised and individuals with an immunologically immature immune system. There are no licensed vaccines available against HCMV and current therapeutic approaches that target key viral proteins are highly toxic with antiviral drug resistance emerging rapidly in HCMV. Thus, targeting host genes and pathways that are essential for viral infection offers an alternative antiviral strategy. I show that HCMV requires host oxidative immune responses for efficient viral replication. Accumulation of reactive oxygen species (ROS) drives intracellular oxidative stress responses. Using a panel of ROS scavengers, I identified that peroxynitrite, a potent oxidant and nitrating agent, enhanced viral replication in both in vitro and in vivo models of CMV. Inhibition of peroxynitrite prior to or at the onset of HCMV infectionalleviates viral replication in both cell-free and cell-to-cell infection systems, indicating that peroxynitrite may impact virus entry and/or the initiation of replication. Additionally, I conducted a genome-wide assessment of host factors and identified six novel genes (NF2, KIRREL, MED23, LATS2, C16orf72 and KIF5B) as essential for HCMV infection required for HCMV replication. Three of these unique hits are known to be involved in Hippo signalling. Preliminary experiments demonstrated that inhibition of the Hippo pathway dramatically reduced the production of infectious progeny. However, additional functional assays are required to elucidate the underlying molecular mechanisms by which these factors support HCMV replication. Nonetheless, this thesis identifies several potential proviral host factors that could possibly be targeted by pharmacologic treatments to combat HCMV.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	19 July 2022
Last Modified:	19 Jul 2023 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/151361

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