Investigation of transmission of human respiratory pathogens using whole genome sequencing
Date
2023-06-20Author
Stapleton, Patrick
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Abstract
This doctoral thesis explores the role of whole genome sequencing in the investigation of
transmission of human respiratory pathogens. It is a “PhD thesis by publication” which consists
primarily of three published first-author journal articles that describe investigations of the
transmission of Mumps virus, Adenovirus and Pseudomonas aeruginosa respectively. The work was
undertaken in Toronto, Canada between 2016 and 2019, when the author was a Clinical and
Research Fellow in Medical Microbiology at the University of Toronto, the Hospital for Sick Children
and the Public Health Ontario Laboratory, as well as a PhD student with University of Galway
supervised by Prof. Martin Cormican. The topics of the research were chosen for (1) their relevance
to public health or hospital outbreak prevention and infection control and (2) as contexts in which
best practices had yet to be established for genomic epidemiology investigations using whole
genome sequencing. The majority of infections described occurred in the greater Toronto area.
The introduction outlines the development of early generation pathogen typing techniques and the
advent of low-cost and widely distributed whole genome sequencing technologies. The strengths
and limitations of sequencing technologies that have seen widespread adoption in the field of
clinical microbiology are described. An outline of the epidemiological context for each of the three
articles is provided, along with rationales for using sequencing to explore transmission. The focus of
the publications consists of (1) investigating the community spread of a Mumps virus outbreak in
Ontario, (2) investigating a prolonged nosocomial outbreak of human Adenovirus-A31 affecting a
paediatric bone marrow transplantation unit over 3 years and (3) the retrospective interrogation of a
large collection of P. aeruginosa isolates from children with Cystic Fibrosis to identify cryptic
nosocomial transmission.
The discussion section that follows the main chapters describes how the findings from all
investigations illustrate the need for clinicians to employ an approach to genomic epidemiology that
can define thresholds for relatedness between pathogens where this has not already been clearly
established, in order to “rule in” or “rule out” transmission as the core finding. The novelty and
significance of specific findings from each study are identified and commonalities between them
discussed. Finally, a post-script section explores how the lessons learned can be applied to the
integration of whole genome sequencing into the routine work of clinical microbiology in hospitals
laboratories in Ireland to support outbreak investigation. It briefly describes how initial steps
towards this integration taken during the course of the Covid-19 pandemic through the setup of a
national laboratory network for whole genome sequencing of SARS-CoV-2.