Advisor(s)
Carlos Orihuela
Committee Member(s)
Elliot Lefkowitz
Martin Young
Megan Kiedrowski
Michael Gray
William Swords
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Microbiology
Date of Award
9-11-2025
Abstract
During invasive disease, certain strains of Streptococcus pneumoniae (Spn) can invade the myocardium, damaging cardiomyocytes and predisposing patients to life-threatening cardiac complications. To identify genetic loci involved in pneumococcal cardio-virulence, we performed a bacterial genome-wide association study using 825 genomes corresponding to 17 distinct Spn lineages associated with varying rates of cardiac complications during hospitalization for pneumonia. This led to the identification of an allele of zmpB, the gene encoding Zinc metalloprotease B (ZmpB). Infection of mice with a ZmpB deficient mutant, i.e., TIGR4ΔzmpB, found that ZmpB was required to form foci of infection in the heart, i.e., cardiac microlesions. ZmpB was confirmed to be present on the bacterial surface, produced during infection within the heart, and to be secreted following the cleavage of its N-terminus. Mice immunized with recombinant ZmpB and then challenged with Spn were protected against cardiac damage, but not bacteremia. Infection of 3-dimensional cardiac organoids with Spn affirmed that infection impaired cardiomyocyte contractility in vitro and that ZmpB impacted myocardial survival odds. Further investigation showed ZmpB deficiency negatively impacted Spn invasion of and survival within cardiovascular endothelial cells and cardiomyocytes independent of adhesion. The N-terminus of ZmpB varied between strains based on the presence or absence of repeated FIVAR domains; with genetic lineages associated with high-incidence of cardiac complications having higher numbers of FIVARs. Infection of mice with clinical isolates and isogenic mutants encoding different alleles of zmpB showed those with more FIVAR domains formed cardiac microlesions at greater rates. Moreover, an isogenic mutant of Spn carrying ZmpB with the FIVAR domains deleted was attenuated for invasion into endothelial cells and microlesion formation in vivo. Our results indicate that Spn lineages carrying FIVAR domains within their ZmpB have a higher propensity for cardiac damage due to their improved ability to cross endothelial cell bottlenecks.
ProQuest ID
Recommended Citation
Luck, Jennifer Nichelle, "Lineage-Associated Zinc Metalloprotease B And Its Impact On Cardiac Damage Elicited During Invasive Pneumococcal Disease" (2025). All ETDs from UAB. 7392.
https://digitalcommons.library.uab.edu/etd-collection/7392
