Saint Louis University researchers are studying how fetal exposure to inflammation can alter immune responses after birth.
Joyce Marie Koenig, M.D., professor of pediatrics and molecular microbiology & immunology at Saint Louis University, and a SLUCare neonatologist at SSM Health Cardinal Glennon Children's Hospital, is the recipient of a $412,500 grant from the National Institutes of Allergy & Immunology. She and her collaborators will examine the link between chorioamnionitis, a common inflammation of the placenta, and immunity after birth.
On November 17 -- World Prematurity Day -- the World Health Organization issued several sobering facts: One in 10 pregnancies lead to the delivery of preterm babies, meaning that each year, 15 million babies worldwide will be born too early. Preterm birth is the primary cause of death in children less than 5 years of age. Over 1 million babies die each year due to complications of prematurity.
"Unfortunately, the number of preterm births is going up, for reasons that we don't completely understand," Koenig said. "Although advances in neonatal medicine have improved the survival of extremely preterm babies, many survivors will still have serious health issues that may be life-long. We have a mandate to better understand the causes and possible preventions of prematurity and its associated complications in newborns."
One clue relates to chorioamnionitis, an important cause of preterm birth: up to 70 percent of extremely preterm babies are born after this inflammatory disorder.
Chorioamnionitis is a bacteria-caused inflammation in the placenta that can lead to inflammatory injury of the brain, lungs and intestines in preterm babies. Preterm babies born after pregnancy inflammation are also at high risk for later infections, and some evidence suggests they may be less responsive to vaccinations. However, how this occurs and whether exposure to inflammation is an underlying cause is unclear.
"Inflammation is the body's response to an insult or injury," Koenig said. "It's an important way for the body to fight infection.
"During infection, bacterial signals initiate a protective inflammatory response. These signals activate and attract immune cells, such as neutrophils, that function as 'first responders' in infected tissues. After these cells ingest and kill bacteria, they are removed by macrophages, the immune cleanup crew.
"However, in some cases, the inflammatory response continues even after the infection has been cleared. This can result in persistent inflammation, which even if it occurs at a low level, could continue to cause problems. We think that chorioamnionitis is partly due to just such a persistence. So, it's really key to try to understand that process to nip it in the bud.
"We get inflammatory insults throughout our lives, and we assume we get over them. But, perhaps we don't. Inflammatory insults, especially when they occur in the fetus, may possibly reset the developing immune program and affect immunity throughout life."
This possibility is suggested by studies showing a link between fetal exposure to inflammation and asthma later in childhood.
"One of the most important set of questions we're asking is 'What's good inflammation, protecting against infection, what's bad inflammation, causing injury to tissues and organs, and how do you target the bad without hurting the good?'"
There are two main, functionally interdependent arms to the immune system, Koenig explains. These involve innate and adaptive immune responses.
"The innate immune system represents cells, such as neutrophils, that respond quickly to bacterial invasion. Adaptive immunity typically depends on the slower development of responses, such as antibodies, to protect the host against specific bacteria and other pathogens. Several innate and adaptive immune cells are unique in that they can bridge the functions of the adaptive and innate immune systems. For example, the adaptive Th17 cell subset can interact with neutrophils to amplify inflammation."
In a previous study funded by The Gerber Foundation and in collaboration with professor and chair of pathology Carole Vogler, M.D. and SLUCare physicians at SSM Health St. Mary's Hospital Christopher Buchanan, M.D., assistant professor of obstetrics, gynecology and women's health at SLU and Gilad Gross, M.D., professor of obstetrics, gynecology and women's health at SLU, the Koenig team found that both mothers with pregnancy inflammation and their preterm babies had high numbers of circulating Th17 cells. Th17 cells are critical to a healthy immune system, but under inflammatory conditions can cause injury to important organs, such as the brain or lungs. Whether and how these Th17 cells influence immune responses in infants born after pregnancy inflammation is presently unknown.
Koenig will use her NIH grant to explore several questions: Are the elevated Th17 cells in pregnancy inflammation pathologic, directly causing tissue damage? Are they protective against infection? Or, are they just a marker of inflammation? If a baby has this inflammatory response, will it affect their immune system? What causes Th17 cells to increase and what drives their function during pregnancy inflammation? Does this involve microRNAs, small non-coding RNAs that serve to turn genes on and off?
To address these questions, Koenig is leading a multi-disciplinary, cross-campus team that includes Ángel Baldán, Ph.D., associate professor of biochemistry, Stephen Barenkamp, M.D., professor of pediatrics and molecular microbiology & immunology, Laurie Shornick, Ph.D., associate professor of biology and Daniel Hoft, M.D., Ph.D., professor of internal medicine and director of the Saint Louis University Center for Vaccine Development.
Using a mouse model of pregnancy inflammation and genetically modified mice, the team will study how fetal exposure to inflammation affects natural and vaccine-induced protective immunity against infections, with a focus on Th17 cells. Learning how inflammation might subvert immune responses could lead to strategies that promote healthier human pregnancies and healthier babies.
Koenig is interested in other connections, as well. Previous studies have found correlations in animal models between chorioamnionitis and health issues later in life, including heart disease and behavioral abnormalities.
Though her research is conducted in the laboratory, Koenig's focus begins and ends with her work in the newborn intensive care unit (NICU) at SSM Health Cardinal Glennon Children's Hospital. As a physician scientist, Koenig's research is driven by her experiences while caring for babies.
"Every time I work in the NICU, I come back to my laboratory with new questions. I see something, I ask why does this happen, I read to come up with ideas, and I then start testing in the laboratory."
Through her research, Koenig hopes to answer these questions and discover new avenues for treatments for her littlest patients.