Allele-specific zinc metalloprotease B influences cardiac damage during invasive pneumococcal disease

During severe infection, Streptococcuspneumoniae invades the myocardium, causing life-threatening cardiac complications. Bacterial genome-wide association studies implicate a specific allele of the gene encoding zinc metalloprotease B (ZmpB) as a key determinant of S. pneumoniae-mediated cardiac damage. In mouse models, ZmpB-deficient S. pneumoniae show reduced cardiac microlesion formation, and immunization with recombinant ZmpB confers protection. ZmpB-deficient S. pneumoniae are also attenuated in their ability to impair contractility of human induced pluripotent stem cell (iPSC)-derived 3D cardiac organoids and exhibit reduced invasion and intracellular survival in mouse cardiac vascular endothelial cell (MCEC) and atrial cardiomyocyte (HL-1) cell lines. ZmpB varies in the number of FIVAR (found in various architectures) domains at its N terminus, with FIVAR-rich variants being prevalent in strains linked to human cardiac complications. Using clinical isolates and isogenic mutants producing ZmpB with different FIVAR domain counts, we confirm this association. These findings indicate that FIVAR-rich ZmpB variants enhance S. pneumoniae's invasive capacity, increasing the risk of cardiac pathology.