Pneumonia, a disease that takes a heavy toll on healthcare systems, is responsible for over 1.2 million emergency room visits annually in the US and claims the lives of more than 41,000 adults. Globally, it tragically takes the lives of over one million children under the age of five each year. While previous research has focused on the lungs, pneumonia can also trigger life-threatening heart complications, including heart failure, arrhythmias, and heart attacks.
Researchers from the University of Maryland School of Medicine (UMSOM) and the University of Alabama at Birmingham's Heersink School of Medicine have made a groundbreaking discovery. They've identified a bacterial enzyme, zmpB, which may be the key to understanding why some individuals experience heart complications with pneumonia while others do not. Enzymes are crucial for bacterial survival, growth, and sometimes, tissue attack, making zmpB a potential target for future vaccines and drug therapies. Their findings were published in Cell Reports on December 4.
"Approximately one in five individuals hospitalized with pneumonia will suffer a life-threatening cardiac event, and even years later, they are at least twice as likely to experience some form of heart failure," explained the study's lead author, Carlos J. Orihuela, PhD, Professor of Microbiology at the University of Alabama at Birmingham.
While pneumonia can be caused by various bacteria and viruses, the team focused specifically on Streptococcus pneumoniae, the leading cause of community-acquired pneumonia. Using bacterial genome-wide association studies (bGWAS), mouse models, and cardiac organoids, they confirmed that S. pneumoniae can directly damage the heart and that zmpB plays a crucial role in facilitating the invasion of S. pneumoniae into the heart.
"This role for zmpB is entirely new, and now it's a potential treatment target," Orihuela emphasized.
Adonis D'Mello, PhD, a Bioinformatics Analyst in the group of Hervé Tettelin, PhD, Professor of Microbiology and Immunology at UMSOM and the Institute for Genome Sciences, further explained: "When we examined strains isolated from patients who developed heart complications and compared them to those who only experienced pneumonia, a clear pattern emerged. Patients with heart failure were more frequently infected with an S. pneumoniae version carrying the zmpB gene, which has a distinctive genetic trait called FIVAR domains. These domains are special segments that help the bacteria invade and survive within heart cells, causing pockets of infection. Interestingly, the more FIVAR domains this gene has, the more damage it causes to the heart."
The researchers infected mice with either a regular pneumonia strain or a genetically modified strain where the zmpB gene was knocked out. They monitored disease progression and found that mice infected with the normal strain developed numerous cardiac microlesions and cell death, damaging the heart. In contrast, those infected with the knocked-out strain had minimal to no microlesions or cell death around their hearts.
Next, they exposed heart organoids, beating cardiac cells grown from human stem cells in a petri dish, to three tests: infection with pneumococcal strains with and without the zmpB gene and different versions of zmpB. The results showed that zmpB with attached FIVAR domains invaded heart cells, while those lacking FIVAR domains had reduced heart tissue cell death and bacterial entry.
Dr. Tettelin commented, "With the mouse models, we learned that injury to the heart depended on the zmpB expressed by the strain, and with the organoids, we learned that it happens because the proteins equipped with FIVAR domains help bacteria invade heart cells and damage them."
"Our goal is to better protect patients against the risk of heart damage during pneumonia or at least minimize its severity by understanding these molecular fingerprints," Dr. Orihuela said. "While more research is needed before clinical application, it may be possible for doctors to identify high-risk bacterial strains early in an infection through a simple genetic test, allowing for closer cardiac monitoring or targeted treatment to prevent heart damage."
Mogens Kilian DMD, DSc, Dr. hc, FKC, R1, Professor Emeritus of Medical Microbiology at Aarhus University in Denmark, who is an expert in the field but did not participate in this research, praised the findings: "Not only does the study identify a function of an enigmatic enzyme in Streptococcus pneumoniae, but it also explains the pathogenesis of serious complications associated with infections caused by some strains of this pathogen, opening a potential route to prevention."
Source: Cell Reports, DOI: 10.1016/j.celrep.2025.116574
