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Cell wall of pneumonia bacteria can cause brain and heart damage
October 25, 2006Investigators at St. Jude Children's Research Hospital have discovered in mouse models how cell walls from certain pneumonia-causing bacteria can cause fatal heart damage; researchers have also shown how antibiotic therapy can contribute to this damage by increasing the number of cell wall pieces shed by dying bacteria. The team also demonstrated in a mouse model how to prevent this from happening.
The study shows that pieces of cell walls from Streptococcus pneumoniae bacteria "hijack" a protein on the lining of the blood vessel wall and use it to slip out of the bloodstream and into the brain and heart. A report on this study appears in the November 1 issue of the Journal of Immunology. These findings explain why blood stream infection with S. pneumoniae commonly leads to temporary impairment of heart function, and they suggest a way to prevent that from occurring, according to Elaine Tuomanen, M.D., chair of the St. Jude Department of Infectious Diseases. S. pneumoniae is a leading cause of pneumonia, sepsis (a potentially life-threatening bloodstream infection) and meningitis (inflammation of the membranes surrounding the brain and spinal cord).
The St. Jude team found that pieces of cell wall from S. pneumoniae that escape from the bloodstream enter neurons (brain cells). In a previous report published in the July issue of Infection and Immunity, St. Jude researchers reported that in the mouse model, cell wall fragments damaged neurons in the part of the brain called the hippocampus. Tuomanen is senior author of both reports.
In the current study, the researchers showed how the cell wall fragments escape the bloodstream and enter cells. Specifically, they demonstrated that pieces of the bacterial cell wall bind to the vascular endothelium (inner surface of the blood vessel) by hooking onto a protein called platelet activating factor receptor (PAFr). Platelet activating factor (PAF) is an immune system signaling molecule that activates certain white blood cells. It normally binds to PAFr on the cell lining. The St. Jude team demonstrated that phosphorylcholine, a molecule on the bacteria's cell wall, resembles PAF and exploits this similarity to bind to PAFr.
The researchers demonstrated the role of PAFr by injecting fragments of S. pneumoniae cell wall into normal mice as well as mice that lacked the gene for PAFr (Pafr-/- mice). None of the regular mice survived after eight hours, and cell wall was found in their hearts and brains. However, all of the Pafr-/- mice survived and almost no cell wall was found outside the blood stream. This suggests that PAFr is required for cell walls to escape the bloodstream and enter cardiomyocytes (heart muscle cells) and neurons. Moreover, cell wall fragments lacking phosphorylcholine did not bind to the inner lining of the blood vessels of the animal models, a finding that demonstrates S. pneumoniae cell walls use this molecule to latch onto PAFr.
"S. pneumoniae have learned how to exploit PAFr and use it as a ferry to cross the endothelium of the blood vessels and escape from the bloodstream," Tuomanen said. "From there they enter the cardiomyocytes or neurons in the brain by binding to PAFr on those cells as well."
The investigators used laboratory culture studies to show that while neurons and endothelial cells remained healthy after cell wall uptake, a rapid decline occurred in cardiomyocytes' ability to contract as they do in the heart. The researchers were able to block this effect by first treating the cardiomyocytes with a molecule called CV-6209, which blocked PAFr, preventing the cell wall from binding to it. In fact, mice pretreated for 16 hours with CV-6209 survived, while mice treated after inoculation of cell wall did not.
"Our success in preserving cardiomyocyte function even in the presence of cell wall suggests that it might be possible to safely pre-treat people infected with S. pneumoniae with a drug that blocks PAF before we administer antibiotics," Tuomanen said. "This might protect the heart from the build-up of cell wall fragments released from bacteria killed by the antibiotic."
Tuomanen's team has also developed evidence that explains how the S. pneumoniae cell wall binds to PAFr on the surface of endothelial cells, neurons and cardiomyocytes and triggers a cascade of biochemical signals called the PAFr-beta-arrestin 1 pathway. The St. Jude researchers reported that this pathway is responsible for bacterial uptake into these cells. Furthermore, the researchers succeeded in blocking a key enzyme of this pathway in cardiomyoctyes using a molecule called PLC inhibitor U73122. The treatment prevented the cell from taking up the fragments but did not appear to interfere with the cell's normal functions. This suggests that a drug that blocks the pathway responsible for pulling cell fragments into the cell might not have serious side effects on the cell.
St. Jude Children's Research Hospital
In the current study, the researchers showed how the cell wall fragments escape the bloodstream and enter cells. Specifically, they demonstrated that pieces of the bacterial cell wall bind to the vascular endothelium (inner surface of the blood vessel) by hooking onto a protein called platelet activating factor receptor (PAFr). Platelet activating factor (PAF) is an immune system signaling molecule that activates certain white blood cells. It normally binds to PAFr on the cell lining. The St. Jude team demonstrated that phosphorylcholine, a molecule on the bacteria's cell wall, resembles PAF and exploits this similarity to bind to PAFr.
The researchers demonstrated the role of PAFr by injecting fragments of S. pneumoniae cell wall into normal mice as well as mice that lacked the gene for PAFr (Pafr-/- mice). None of the regular mice survived after eight hours, and cell wall was found in their hearts and brains. However, all of the Pafr-/- mice survived and almost no cell wall was found outside the blood stream. This suggests that PAFr is required for cell walls to escape the bloodstream and enter cardiomyocytes (heart muscle cells) and neurons. Moreover, cell wall fragments lacking phosphorylcholine did not bind to the inner lining of the blood vessels of the animal models, a finding that demonstrates S. pneumoniae cell walls use this molecule to latch onto PAFr.
"S. pneumoniae have learned how to exploit PAFr and use it as a ferry to cross the endothelium of the blood vessels and escape from the bloodstream," Tuomanen said. "From there they enter the cardiomyocytes or neurons in the brain by binding to PAFr on those cells as well."
The investigators used laboratory culture studies to show that while neurons and endothelial cells remained healthy after cell wall uptake, a rapid decline occurred in cardiomyocytes' ability to contract as they do in the heart. The researchers were able to block this effect by first treating the cardiomyocytes with a molecule called CV-6209, which blocked PAFr, preventing the cell wall from binding to it. In fact, mice pretreated for 16 hours with CV-6209 survived, while mice treated after inoculation of cell wall did not.
"Our success in preserving cardiomyocyte function even in the presence of cell wall suggests that it might be possible to safely pre-treat people infected with S. pneumoniae with a drug that blocks PAF before we administer antibiotics," Tuomanen said. "This might protect the heart from the build-up of cell wall fragments released from bacteria killed by the antibiotic."
Tuomanen's team has also developed evidence that explains how the S. pneumoniae cell wall binds to PAFr on the surface of endothelial cells, neurons and cardiomyocytes and triggers a cascade of biochemical signals called the PAFr-beta-arrestin 1 pathway. The St. Jude researchers reported that this pathway is responsible for bacterial uptake into these cells. Furthermore, the researchers succeeded in blocking a key enzyme of this pathway in cardiomyoctyes using a molecule called PLC inhibitor U73122. The treatment prevented the cell from taking up the fragments but did not appear to interfere with the cell's normal functions. This suggests that a drug that blocks the pathway responsible for pulling cell fragments into the cell might not have serious side effects on the cell.
St. Jude Children's Research Hospital
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