ORCID
https://orcid.org/0000-0002-6147-001X
Date of Award
8-18-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Pneumonia remains a major cause of childhood mortality, especially in under-resourced communities. The profound morbidity of pediatric pneumonia in Papua New Guinea (PNG) compels innovative approaches to ameliorate disease. While the high incidence of pneumonia has been ascribed to environmental factors, we here identify a heritable allele increasing risk of severe pneumonia. In a pilot study, whole exome sequencing reveals a single nucleotide variant (SNV) in coenzyme Q6 (COQ6), a mitochondrial enzyme essential for ubiquinone biosynthesis. Significant association of SNV homozygosity with pneumonia replicates in an independently recruited cohort (p=0.036). Mice homozygous for the murine variant exhibit increased mortality after pneumococcal lung infection, confirming causality. Myeloid cell-intrinsic defects include disrupted mitochondrial metabolism, altered inflammatory responses, and impaired intracellular bacterial killing, despite preserved ubiquinone biosynthesis. Identification of this COQ6 variant provides a genetic basis for increased pneumonia susceptibility in PNG and establishes a previously unrecognized role for COQ6 in regulating inflammation.
Language
English (en)
Chair and Committee
Sharon Morley
Recommended Citation
Walker, Emma Catherine, "A Thesis on the Human Genetic Basis of Severe Pneumococcal Infection in Papua New Guinea" (2023). Arts & Sciences Electronic Theses and Dissertations. 3139.
https://openscholarship.wustl.edu/art_sci_etds/3139