Human Parainfluenza Virus 3: Genetic Diversity, Virulence and Antiviral Susceptibility

Human parainfluenza 3 (HPIV3) is a member of the Paramyxoviridae, a single strain negative-sense non-segmented RNA virus in the order Mononegavirales. It is a respiratory pathogen with a broad spectrum of presentations for which there is currently neither a vaccine nor licensed treatment for HPIV3. To date most research on HPIV3 has been conducted using significantly culture adapted reference strains. Therefore, minimally adapted clinical strains were grown in two cell culture systems: immortalised and primary. Plaque phenotype, growth kinetics and inflammatory response triggered were evaluated and it was found that there is a range of phenotypes exhibited by clinical strains with potential implications in vivo. To examine the genetic diversity of circulating strains of HPIV3 in the UK, a new amplicon based sequencing pipeline for whole genome sequencing of HPIV3 was developed and validated. A short hypervariable region in the HPIV3 genome was identified and evaluated as a potential candidate for subsequent phylogenetic analysis compared to whole genome data. This method was then applied to tracking an HPIV3 outbreak that took place on a paediatric oncology ward. It was found to be a point-source outbreak and the clinical impact in this setting, as well as the infection control procedures involved were evaluated. Finally a robust in vitro model for the evaluation of potential therapeutic candidates for HPIV3, based on a panel of minimally passaged clinical strains as well as a culture-adapted reference strain, was set up. This model was applied to three potential inhibitors of HPIV3: ribavirin, favipiravir and zanamivir. The results showed that clinical strains were at least as susceptible to ribavirin and favipiravir as the laboratory reference strain and significantly more susceptible to zanamivir. This indicates that further work on minimally adapted clinical strains is essential to further the understanding of this important virus.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Smielewska, Anna Alexandra

Advisors dc:contributor.advisor

• Goodfellow, Ian
• Jalal, Hamid

• Human parainfluenza 3
• genetic diversity
• antiviral susceptibility
• virulence

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/35303750-7985-4e6a-9154-0cb7c9fe0163/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.35272

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/287954