(From the March 2015 Issue of PediatricsOnline)
Understanding the surface features of the bacteria that are a leading cause of community-acquired pneumonia and ear infections may hold the key to a new therapeutic target for a wide range of diseases. According to a study by scientists in The Research Institute at Nationwide Children’s Hospital, Streptococcus pneumoniae and many other pathogens have a protein on their surface that helps them bind to carbohydrates on the surface of host cells, which is a critical step in infectious disease development. Researchers demonstrated that interrupting this mechanism reduces the bacteria’s ability to bind to host cells, which may potentially prevent colonization and reduce the likelihood of infection.
“Theoretically, this type of inhibition of binding between pneumonia-causing bacteria and the epithelial cells of the host could be a game-changer,” says Octavio Ramilo, MD, chief of infectious diseases at Nationwide Children’s and senior author on a recent paper on community-acquired pediatric pneumonia published in The Journal of Infection. “Additional research will help determine whether this opens the field of medicine to an entirely new class of therapeutics with much broader potential clinical applications than just pneumonia.”
S. pneumoniae is responsible for many of the millions of cases of community-acquired pneumonia worldwide each year. Traditionally, researchers believed that a large portion of the pathogen, called β-galactosidase BgaA, was located on the bacterial cell surface simply to cleave host carbohydrates for nutritional purposes. But recently, a team led by Samantha J. King, PhD, principal investigator in the Center for Microbial Pathogenesis at Nationwide Children’s, discovered that the protein also played a role in adherence — binding the bacteria to host cells. This suggestion helped guide the team, toward a surprising discovery.
“We found the first evidence that a previously unstudied domain of the protein serves to bind carbohydrates on the surface of host epithelial cells,” says Dr. King, senior author on the paper, which was published in PLOS Pathogens. “This domain, called carbohydrate-binding molecule or CBM, is common among surface proteins, so our findings could also apply to a wide range of other infection-causing bacteria.”
|This figure shows the binding of previously unstudied domain of S. pneumoniae protein BgaA to a receptor on the host cell surface. The center image demonstrates how this function could feasibly be blocked by supplying analogues that mimic the receptor, while the right image demonstrates how supplying blockers that adhere to the host cell receptor could also prevent binding. The team suggests these methods could enable novel therapeutic interventions for pathogens such as S. pneumoniae.|
Dr. King and her team believe that creating molecules that mimic either CBM or carbohydrates on the host cell could inhibit binding, colonization and eventual infection.
“Binding or bacterial adherence to the host cells is critical for infectious disease to take root,” says Anirudh K. Singh, PhD, a post-doctoral fellow in Dr. King’s lab and lead author on the study. “By verifying that interrupting the CBM mechanism leads to reduced binding, we identified a new avenue for therapeutic intervention. It’s a new paradigm for how scientists understand CBMs.”
Visualization techniques helped the researchers fine-tune their understanding of the CBM on the surface of S. pneumoniae and may also inform the design of therapies based on the concept of blocking the CBM from binding to host cells.
“If we know the structure of a pathogen’s surface and how it binds to a host cell — like a key to a lock — we can effectively create a sort of duplicate key,” Dr. Singh explains. “That way, when the bacteria try to adhere to a host cell, the lock is already filled and they have to move on. You can use molecules that are very similar to block the interaction.”
According to Dr. King, clinical therapies based on this blocked interaction are a long way off, however. The team’s tests were performed in cell lines and primary cells that included human lung cells, but a good in vivo animal model has yet to be found due to the human-specific nature of the S. pneumoniae pathogen. Furthermore, practical barriers, such as variations in the exact proteins and carbohydrates in play, may make it hard to target some strains of bacteria. These challenges may mean that other diseases will be the first to benefit from this initial research on Streptococcus pneumoniae.
“The therapeutic potential of blocking this mechanism of bacterial adherence is not restricted to pneumonia or pulmonary conditions,” Dr. King says. “We believe the bacteria that cause endocarditis, an infection in the heart, might actually be an easier target for inhibiting adherence in a clinically promising way.”
The team is currently working to patent a CBM that will block the adherence of bacteria that cause endocarditis. They have already determined that the technique is effective in cell lines and will be moving onto a rat model of the disease.
“S. pneumoniae may have given birth to this therapeutic concept, but the next round of advancements may have to take place with a species where this adherence mechanism can be modeled in vivo,” Dr. King says. “Ideally, this new approach to infectious disease therapeutics would come full circle and impact the treatment of community-acquired pneumonia.”
Singh AK, Pluvinage B, Higgins MA, Dalia AB, Woodiga SA, Flynn M, Lloyd AR, Weiser JN, Stubbs KA, Boraston AB, King SJ. Unravelling the multiple functions of the architecturally intricate Streptococcus pneumoniae β-galactosidase, BgaA. PLoS Pathogens. 2014 Sep 11, 10(9):e1004364.
Wallihan R, Ramilo O. Community-acquired pneumonia in children: current challenges and future directions.The Journal of Infection. 2014 Nov, 69 Suppl 1:S87-90.