Research suggests common viral infection worsens deadly condition among premature babies

The research team, led by Johns Hopkins Children's Center investigators and funded by the National Institutes of Health, says the new findings advance the search for better treatments for NEC -- a relatively rare condition, but still the most common emergency intestinal complication in preemies.

A report on the study published Feb. 13 in Cellular and Molecular Gastroenterology and Hepatology.

"NEC is the most important disease that most people have probably never heard of. The impact of this disease on premature infants and their families is great, and is made worse by the fact that people often hear about NEC for the first time only after their loved one is diagnosed with it. Surprisingly, we often don't actually know what causes NEC in the first place. By identifying its connection with cytomegalovirus infection, we have now identified an important trigger for NEC, which could save the lives of premature infants who develop this condition," says David Hackam, M.D., Ph.D., Garrett Family Professor of Pediatric Surgery at the Johns Hopkins University School of Medicine and surgeon-in-chief and co-director of Johns Hopkins Children's Center.

Up to nearly 10% of premature infants develop NEC, a disease characterized by severe inflammation of the intestinal lining that ultimately kills this tissue. About a third of babies with NEC ultimately die from it, and survival rates have remained unchanged over the past three decades.

Recent research in animals, Hackam says, has shown that NEC's trademark inflammation is at least partly due to a persistent uptick in an immune protein called toll-like receptor 4 (TLR4), which becomes activated by the abnormal accumulation of specific intestinal bacteria that tend to overgrow in the digestive tract of premature infants. But why NEC is more severe in some babies and tends to be spreadable has been a mystery.

That led to CMV as a suspect, Hackam says.

An estimated 40% to 80% of people worldwide are chronically infected with cytomegalovirus, a virus in the herpes family that doesn't usually cause symptoms in healthy people but is a common cause of hearing loss and other organ-damaging birth defects when transmitted from mother to fetus during pregnancy. Fetuses acquire CMV from infected mothers during gestation in 30%-50% of cases.Suspecting a connection between CMV and NEC severity, Hackam and his colleagues developed a neonatal mouse model of NEC with CMV. When they compared the intestines of the rodents with and without CMV infection, they found that mice harboring CMV had significantly worse tissue damage and higher mortality rates compared to those without this virus.

Searching for a molecular mechanism for this outcome, the researchers compared gene activity in the intestines of the two groups of mice. They found that CMV infection triggered genetic pathways that encouraged inflammation, disrupted metabolism and prompted cells to make more TLR4.

A closer look showed that CMV also damaged mitochondria, organelles that serve as cells' energy factories. The damage significantly decreased mitochondrial production of adenosine triphosphate (ATP), a molecule that cells use for fuel.

Further experiments with mouse tissue, Hackam noted, showed that TLR4 was necessary for each of these effects. Mice genetically altered to produce no TLR4 in their intestines, for example, had significantly lower NEC severity even with CMV infection, suggesting that this protein could be a good target for developing drugs against NEC.

If animal and human studies confirm the CMV-NEC connection, another treatment option might be to administer adenosine, Hackam explains, a precursor for ATP that's commonly sold as a dietary supplement. When the researchers gave mice with NEC and CMV adenosine, it significantly reduced NEC severity. The team plans to investigate these ideas in future studies.

Other Johns Hopkins researchers who contributed to this study include Chhinder P. Sodhi, Daniel Scheese, Peng Lu, Hannah Moore, Koichi Tsuboi, Cody Tragesser, Johannes Duess, Zachariah Raouf, Maame F. Sampah, Daphne Klerk, Mahmoud El Baassiri, Hee-seong Jang, Sierra Williams-McLeod, Asuka Ishiyama, Steve N. Steinway, Sanxia Wang, Menghan Wang, Thomas Prindle Jr., and William B. Fulton.

This study was funded by grants from the National Institutes of Health (R35 GM141956 and T32 DK007713) and the Garrett Fund for the Surgical Treatment of Children at The Johns Hopkins University.

Hackam and Sodhi hold patents for the development of novel agents to inhibit TLR4 for the prevention and treatment of NEC.

For more information about Johns Hopkins research and how it saves lives, visit the Johns Hopkins University Hub website.