Investigating the role of host proteins in rhinovirus infected cells

Abstract

Rhinovirus (RV) is the most common viral infectious agent in humans and primarily causes the common cold. RV is also a major trigger for acute exacerbations of chronic pulmonary diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. Unfortunately, conventional antiviral approaches focused on targeting RV proteins directly have not led to the development of an approved anti-RV drug. One alternative strategy would be to target host cell proteins that are exploited by RV during infection as this is less likely to lead to the emergence of antiviral resistance. However, current understanding of rhinovirus-host interactions is limited. During infection, RV non-structural proteins (NSPs) interact with host cell proteins, facilitating viral replication and subverting normal host cell functions. Some of these important host cell factors such as GBF1, PI4KIIIβ and SETD3 have already been identified. However, we hypothesised that other host cell proteins are also exploited by RV and their identification would not only improve our current understanding of rhinovirus-host interactions but could eventually provide new cellular targets that could be exploited for antiviral development.

In this study, we demonstrate that two cellular AAA+ ATPases are necessary for the replication of RV-A and RV-C types in both cell lines and well-differentiated primary nasal epithelial cells. We also demonstrate that the siRNA knockdown of some cellular phosphoserine/phosphothreonine binding chaperones partially inhibits RV-A16 replication. In addition, we provide evidence of a highly conserved “Rx[E/D]P” phosphomimetic motif within 2C that is essential for RV replication.

Overall, this project provides evidence for the involvement of some host cell AAA+ ATPases and phosphoserine/phosphothreonine binding chaperones in RV replication and suggests a possible role for them during RV infection, representing a step towards improved understanding of rhinovirus-host interactions.

Thesis is embargoed until 31st December 2029.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Aurelie Mousnier (Supervisor) & Ultan Power (Supervisor)