Creation of Bioinformatics Approaches to Understand Host-Pathogen Molecular Mimicry

Imitation is not the sincerest form of flattery; for some it is the key to survival. Across phyla, pathogens imitating aspects of their host is crucial to their continued survival and proliferation. Also called molecular mimicry, imitation of host biomolecules has been observed to target a wide range of processes, including host signaling pathways and the immune system. Identification of molecular mimicry can provide insights into pathogen virulence and pathogenicity. Additionally, in silico detection methods can predict currently unknown host-pathogen interactions. Here, I describe my development of a bioinformatic method for mimicry detection using protein sequence data, with the ultimate aim to further our collective understanding of molecular mimicry. In Chapter 2, I resurrected and improved upon a bioinformatic k-mer based mimicry detection method, which I assessed on 32 human-infecting pathogens. During my assessment, I exposed potential concerns with the method and recommended avenues for further improvement. Chapter 3 describes my critical evaluation of each step in the pipeline and subsequent development of mimicDetector, a new pipeline for molecular mimicry identification. During my evaluation, I assessed the performance of five protein search tools with two amino acid substitution scoring matrices on varying query lengths. From these results, I determined the combination best suited to mimicry detection and implemented a new filtering method which better assesses similarity between pathogen and host protein sequences. Lastly, in Chapter 4, I applied mimicDetector to a focused investigation of the causative agent of human tuberculosis, Mycobacterium tuberculosis (Mtb). Among my predicted mimics were potentially novel Mtb-human protein interactions as well as a protein frequently implicated in Mtb molecular mimicry. My investigation highlights strategies used by Mtb to subvert host defenses and provides insight into the role mimics play in pathogenicity and virulence.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Veterinary Medical Sciences

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2024

Author dc:creator

• Rich, Kaylee Dawn

Advisor dc:contributor.advisor

• Wasmuth, James D.

Committee members dc:contributor.committeemember

• Gilleard, John
• Lewis, Ian
• Peters, Nathan

• bioinformatics
• protein interactions
• host-pathogen interactions
• parasitology
• infectious disease
• autoimmunity
• pathogenicity
• molecular mimicry
• mycobacteria
• tuberculosis

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

en

DOI

https://dx.doi.org/10.11575/PRISM/47301

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/119690