She remembers him as Baby Branford.
Fresh from pediatric training and immersed in a research fellowship in infectious diseases, Elaine Tuomanen, MD, encountered a little boy with pneumococcal meningitis. This infection causes inflammation of the lining around the brain and spinal cord. Antibiotics killed the bacteria, but the treatment failed.
The 3-year-old died.
That wrenching experience three decades ago became a springboard for a pivotal new finding at St. Jude Children’s Research Hospital. The discovery revolutionizes our understanding of how pneumococcus bacteria survive and flourish. This breakthrough also opens the door for sweeping changes to current vaccines and medicines to attack a worldwide killer of children.
Capsules hold the key
Pneumococcal infections cause mild illnesses such as ear infections and bronchitis as well as life-threatening meningitis, pneumonia and bloodstream infections known as sepsis. These infections claim about 1.6 million people globally each year. More than 800,000 of those deaths are among children, according to the World Health Organization.
Tuomanen, chair of St. Jude Infectious Diseases; postdoctoral fellow Colin Kietzman, PhD; and their colleagues made a discovery about an enzyme called LytA. Long known to be the trigger by which antibiotics cause bacteria to explode and die, LytA has a much different function in the everyday life of bacteria growing in humans. In response to normal molecules made by the immune system to control microbes, the bacterium uses LytA to shed its outer layer, or capsule, promoting its survival.
The research also suggests bacteria can rapidly add or remove capsules as needed to avoid detection and destruction by the body’s immune system.
“I decided if I could better understand the surface of the bacteria, I would use that medical paradigm to take apart how the disease happens and how I could fix it,” Tuomanen says. “I didn’t understand why, if we did everything right, Baby Branford didn’t live. That was the beginning of a long and tortuous road to make his situation treatable, with more survivors.”
Scientists have known for decades that a bacterium can change how thick a capsule is on its surface. After two years of research, St. Jude investigators built on that principle. They found that bacteria have an entire pathway devoted to shedding the capsule off the surface, and that LytA is responsible.
“It’s like changing your winter coat to a summer coat,” Tuomanen explains. “The bacteria have learned that a thick, heavy coat in the lung hinders the ability to invade into the bloodstream, so in response to signals in the lung, pneumococcus activates this enzyme for capsule shedding.
“Surprisingly, the shedding activity of LytA is completely independent of its role in antibiotic killing,” she continues. “Shedding is so important to bacterial life in the host that the bacteria are forced to keep the LytA gene even though losing it would make it resistant to penicillin-induced death.”
Capsule-shedding also sets the stage for dangerous infections. This process makes it easier for pneumococci to invade cells and move into the bloodstream. Once in the blood, the bacteria—also known as Streptococcus pneumoniae—again produce capsules to protect against the body’s basic immune response.
“The bacteria hunker down and tightly adhere to lung surfaces, causing more serious disease,” Kietzman says.
Patience, hard work and victories
These new details radically alter our understanding of pneumococcus. The findings may one day transform the arsenal of vaccines and drugs available to prevent and treat pneumococcal infections.
Most vaccines aimed at pneumococcus currently target its capsule to trigger a protective response. But this strategy won’t work if the capsule is shed off the bacteria’s surface. This explains why current vaccines work well against bloodstream infections where the capsule is thick but are much less effective against pneumonia, where bacteria automatically shed the capsule. Instead, Tuomanen says, vaccines targeting pneumococcal surface proteins should be created. This is already occurring at the Children’s GMP, LLC, on the St. Jude campus as well as by commercial drug manufacturers.
“It will take time for those in the field to understand that vaccines are now going to have to be built differently,” Tuomanen says. “It will be a slow road for the big vaccine companies, and they have a lot to lose since they have established capsule-based vaccines they make billions of dollars on.”
But if she’s tempted toward impatience, Tuomanen need only think about Baby Branford and how far she and her St. Jude colleagues have come.
“Now everything is turned upside down, and we understand much more about what penicillin and other antibiotics can do, and what vaccines can and can’t do,” she says. “Baby Branford—with this information turned into a therapeutic—would never have died. It’s a super victory from my perspective.”
From Promise, Autumn 2016