Modeling sepsis in newborns

Sepsis, or bacterial infection of the bloodstream, is a grave, hard-to-diagnose threat in premature newborns in the NICU. Even when it's detected and treated with antibiotics, its inflammatory effects can harm fragile babies' development.

Now, researchers at Boston Children's Hospital have modeled the effects of sepsis on the unique newborn immune system, using mice. They and others have begun using the model to identify diagnostic markers and better treatments.

The new model is described September 6 in the online open-access journal PLOS ONE (available after publication at: http://dx.plos.org/10.1371/journal.pone.0043897).

Premature infants typically are kept alive with catheters and intravenous lines that are vital for their care, but that also carry a risk of bloodstream infection, most commonly from the bacterium Staphylococcus epidermidis. Preventive measures can now avoid many of these infections, but those that slip through can be hard to spot and treat.

“When infection occurs, it's hard to detect in newborns, who can't speak and, due to their unique immune systems, tend not to have fevers or show clinical signs,” explains Ofer Levy, MD, PhD, of the Division of Infectious Diseases at Boston Children's and senior author on the paper. “There may be irregular breathing or increased heart rate, or the baby may be acting a little 'off,' but these signs are pretty nonspecific. There's a tremendous need for better diagnostics in this field.”

Mouse models of intravenous infections in newborns have been lacking, due to the technical challenge of working with tiny newborn mice. With great manual dexterity, Kenny Kronforst, MD, MPH, a clinical Newborn Medicine fellow working in Levy's lab and first author on the paper, was able to inject live S. epidermidis into the tiny animals' jugular veins, simulating what happens when an IV or catheter infection occurs in an hours-old preemie in the NICU.

The findings surprised the team—and gave hope.

“Newborns have traditionally been considered immunologically immature and distinct from adults in their ability to fight off infection,” says Kronforst, now an attending physician in neonatology at Lurie Children's Hospital of Chicago. “Through our model, we have shown that there is a robust inflammatory response to bacterial challenge even at the earliest hours of life. Additionally, we were able to reproduce many clinical features of sepsis that we see in human infants. Because of these features, our model is ideal for exploring novel diagnostic and therapeutic possibilities—something we're extremely excited about.”

For example, one part of the inflammatory response, also known to occur in human newborns, was increased production of a molecule called Toll-like receptor-2 (TLR2). Levy's team and others are now evaluating TLR2 as a potential biomarker for detecting sepsis, as well as a potential target for treatments to suppress the inflammation.

“We can now try to block TLR2 in our model, to see if we can clear bacteria faster and prevent inflammatory damage,” Levy says.

Even when babies with sepsis are treated with antibiotics, the inflammatory response to the infection can be just as harmful. “Infants spend a lot of energy fighting the infection, and the inflammatory response impairs weight gain,” says Levy.

Impaired weight gain was also seen in the mouse model. A separate study with the model, presented at last May's Pediatric Academic Society meeting, linked increased TLR2 production with another kind of damage: impaired development of the brain's white matter.

“There's an emerging literature showing that having bacteria in the bloodstream is harmful to the newborn brain, and that the inflammatory response harms the brain even if the infection is cleared,” Levy says. “That raises the bar tremendously for detection and treatment.”

Levy and his colleagues have been invited to apply for funding to develop new treatments using their mouse model.

The current study was supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institutes of Health. Coauthors were Christy J. Mancuso, MS, Matthew Pettengill, PhD, Jana Ninkovic PhD, Chad Stevens, MS, and Donald Goldmann, MD, all of the Division of Infectious Disease at Boston Children's Hospital; Melanie R. Power Coombs, PhD, Dalhousie University (Halifax, Nova Scotia); Michael Otto, PhD, NIAID; and Carina Mallard, PhD and Xiaoyang Wang, MD, PhD, University of Gothenburg, Gothenburg, Sweden.

Read about the Levy lab's related work on vaccines for newborns in our News Room and blog.

Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Boston Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children's, visit: http://vectorblog.org/.