Microscopy shows how sepsis from staph infection causes organ failure
Using intravital microscopy, researchers discovered the most important target of the Alpha Toxin and how to neutralize the danger.
Scientists have known for some time that one of the reasons a Staphylococcus aureus (staph) infection is so deadly is that the bacteria send out a toxin, known as Alpha Toxin (AT), which quickly worsens sepsis. Using intravital microscopy, researchers at the University of Calgary Cumming School of Medicine's (CSM) Snyder Institute for Chronic Diseases (Calgary, AB, Canada) have discovered the most important target of the toxin and how to neutralize the danger.
With the microscopy method, the researchers discovered that the toxin causes platelets to respond abnormally in mice. Platelets' primary role is to help stop bleeding in mammals after injury. What's relatively unknown is that platelets also play a role in the body's defenses against bacteria. Normally, platelets coat bacteria to prevent the spread of a microbe throughout the patient. However, during sepsis caused by staph infection, as the amount of toxin in the bloodstream increases, the platelets aggregate to form clumps. Those clumps deposit in the liver and kidneys, causing serious damage and eventually organ failure.
"Once you understand exactly how an infection is impacting the body, you can target treatments to mitigate the infection so that the body can begin to heal," says Paul Kubes, Ph.D., professor in the Department of Physiology & Pharmacology and director of the Snyder Institute. "We knew clots were forming in the organs during sepsis from staph infection. Now we know where and why these clots are forming."
Next, the research team wanted to know whether an antibody that targets the toxin could be effective in preventing platelets from clumping. The researchers started working with drug company MedImmune (Gaithersburg, MD), which is conducting a phase ll clinical trial where an Alpha Toxin antibody that they have developed is given to intensive care unit patients prone to develop pneumonia caused by staph due to long-term use of a ventilator. Early indications are the antibody is effective in preventing lung damage.
"When we introduced the antibody to the bloodstream of the mice during sepsis, we saw an immediate reduction in the amount of clotting," says Bas Surewaard, Ph.D., a postdoc in the Department of Physiology & Pharmacology and first author of the study. "A single dose of the antibody reduced liver damage by 50%. By knocking out the toxin, the platelets could begin flowing in the blood stream again."
The findings help explain why some people who are taking antibiotics to kill staph infection still die from sepsis, because the antibiotics do not neutralize the toxin.
"Knowing how the toxin created by staph target platelets, we can now start looking at other bacteria that cause sepsis to see whether we can uncover a similar pattern and find antibodies that can be effective in those cases," Kubes says.
Full details of the work appear in the journal Cell Host & Microbe.