Mast Cells May Hold Key to Preventing Group B Strep Infection

Group B streptococcus. Credit: NIAID. This work is licensed under a Creative Commons Attribution 4.0 International License.

Mast cells. Few know that mast cells are the first responders of the immune system. Even fewer study their role in group B streptococcus, a widespread bacterial infection that can cause preterm birth, stillbirth or dangerous sepsis in infants.

Many women who have given birth will likely remember the group B strep screening in their third trimester.

“Group B strep is normally found in up to 30% of women, but because it doesn’t cause illness, we don’t think about it until there is a risk in pregnancy,” said Dr. Lakshmi Rajagopal, a principal investigator in the Center for Global Infectious Disease Research at Seattle Children’s Research Institute. “In babies, the infection can lead to serious and deadly health consequences such as pneumonia, sepsis and meningitis.”

To ensure the infection is not transmitted to the baby, women testing positive for group B strep receive antibiotics during labor. However, no therapeutic strategies exist to prevent the incidence of systemic group B strep infection that can occur in babies before labor or after birth.

Rajagopal and Dr. Adrian Piliponsky, a principal investigator in the Center for Immunity and Immunotherapies at Seattle Children’s, believe part of the answer to preventing group B strep may lie in mast cells. In a study published in the Journal of Allergy and Clinical Immunology, the researchers reveal new insight into how mast cells defend against bacterial infections.

Meet the mast cell, the body’s unique first line of defense

As the immune system’s first line of defense, mast cells are innate to almost all human tissue. They stand guard at the body’s entry portals and upon sensing an intruder, selectively release mediators to initiate an immune response.

One well-documented example of this process is when mast cells release histamines in response to allergens. The reaction causes the skin to redden such as in the case of a bug bite.

Yet, little is known about how mast cells protect against infection.

“No other cells do what mast cells do,” said Piliponsky. “We know they don’t ignore the bacteria, so we set out to find what happens when mast cells confront group B strep.”

Mast cells diminish bacteria’s ability to disseminate

Chymase released by mast cells prevents group B strep (GBS) from further colonization in the host. Click image to enlarge.

Building on findings that mast cell mediators contribute to the body’s defense against group B strep infection, the collaborative research team led by Piliponsky and Rajagopal zeroed in on a mast cell mediator known as chymase. Chymase belongs to a class of enzymes known as mast cell proteases that work by breaking bonds in proteins and peptides.

When researchers infected chymase deficient mice with group B strep, they observed an increased susceptibility to systemic infection and higher rates of preterm birth. A closer look showed that chymase cleaved fibronectin, a key component that the bacteria need to thrive.

“The bacteria rely on binding to fibronectin to disseminate,” said Piliponsky. “By breaking down fibronectin, chymase diminishes the ability of group B strep to colonize in the host.”

The resulting infection is less severe when chymase is present, thus requiring only a limited inflammatory response to clear. According to Piliponsky, as the likelihood of damaging inflammation and sepsis in the mother decreases, so does the risk of preterm birth.

The antibacterial action of chymase

The goal of the research is to find new ways to prevent group B strep colonization in women, so there is no risk at all to the baby during pregnancy.

Rajagopal noted the findings suggest that the protective antibacterial effect of chymase may offer a future therapeutic strategy for decreasing group B strep infections and preterm birth.

“Ideally we could prevent group B strep colonization in women, so there is no risk at all to the baby during pregnancy,” said Rajagopal.

Further research is needed to understand the protease’s effect on all strains of group B strep – from the garden variety to the most harmful – as well as its interaction with other cells in the immune system. But Chymase is just one piece of the puzzle. Researchers will also examine how they can manipulate fibronectin to aid in preventing infection.

“This function of mast cells unlocks a potential method to stop group B strep before it ever develops into an infection that threatens life,” said Piliponsky. “Imagine the possibilities if we can apply the same approach to the vast range of other bacteria that use similar mechanisms to colonize.”

Dr. Claire Gendrin, a research scientist in the Rajagopal Lab and Dr. Nick Shubin, a research scientist in the Piliponsky Lab also contributed as lead co-authors on this research.