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Blocking protein in blood may prevent sepsis in premature infants

UF Health researchers have found that blocking a certain protein in the blood with medication could help protect premature infants from sepsis, a common and sometimes deadly infection, according to a new study that combines findings from a mouse model and from premature infants.

“Infants born prematurely commonly experience life-threatening sepsis and die more frequently from infection than people in all other age groups – children, adolescents, adults and the elderly,” said James Wynn, M.D., the study’s lead author and an associate professor of pediatrics in the UF College of Medicine. The findings are published April 29 in the Proceedings of the National Academy of Sciences.

Sepsis, a life-threatening infection, can affect up to six of every 10 babies born prematurely and results in death or major lifelong disability in four of 10 who become infected.

There are no measures to prevent sepsis, Wynn noted, and physicians can only treat the infection with supportive therapies such as antibiotics and IV fluids.

“Beyond antibiotics, medications aimed at reducing death and lifelong disability have been unsuccessful,” he said. “Premature infants’ immune systems are not equipped to handle the environment outside the womb.”

In a mouse model, the team is specifically targeting a protein – interleukin 18, or IL-18 – that can severely damage the intestines in premature infants who have sepsis. Interleukins are small proteins the immune system produces as a means of communication.

The researchers found that high IL-18 levels during sepsis increased levels of another interleukin – IL-17A – that severely and fatally injured the intestine.

In mouse models exposed to IL-18, levels of IL-17A were more than 140 times higher than those not exposed to the protein.

“Using a drug to block IL-17A in the mouse model, we significantly reduced death from sepsis caused by high IL-18 production during sepsis,” Wynn said. “This discovery brings new hope for novel treatments that may reduce intestinal damage and death from sepsis in premature infants.”

Data from neonatal mouse models in the study suggest the same can happen in human infants.

The team also measured blood samples from premature infants. They found that those who were not infected with sepsis already had high levels of IL-18 circulating in their blood. The younger the patient, Wynn said, the higher the levels of the protein.

“Those levels increased even more if the baby became septic,” Wynn said.

“Dr. Wynn and his team have identified a novel signaling pathway that leads to intestinal injury in premature infants,” said Lyle Moldawer, Ph.D., a professor and vice chairman of research in the UF College of Medicine’s Department of Surgery. He is also a co-author of the study. “Doing so opens new therapeutic targets to prevent intestinal injury of neonates during sepsis.”

Next, Wynn and his team hope to understand how blocking IL-17A affects other organs in premature infants who have sepsis.

“In the longer term, we hope our findings can impact other inflammatory diseases in adults and children,” Wynn said. Currently, clinical trials are underway to block IL-17 and IL-18 in other diseases, Moldawer added.

The project is the collaborative effort of the departments of pediatrics at the University of Florida and Vanderbilt University.

It is funded by the National Institutes of Health, National Institute of General Medical Sciences (GM106143).

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18 James Lawrence Wynn, Chris S. Wilson, Jacek Hawiger, Philip O. Scumpia, Andrew F. Marshall, Jin-Hua Liu, Irina Zharkikh, Hector R. Wong, Patrick Lahni, John T. Benjamin, Erin J. Plosa, Jörn-Hendrik Weitkamp, Edward R. Sherwood, Lyle L. Moldawer, Ricardo Ungaro, Henry V. Baker, M. Cecilia Lopez, Steven J. McElroy, Natacha Colliou, Mansour Mohamadzadeh, and Daniel Jensen Moore. PNAS. DOI: 10.1073/pnas.1515793113. Published online before print on April 25, 2016