Researchers have discovered that a prevalent virus capable of being transmitted from mother to fetus before birth significantly exacerbates necrotizing enterocolitis (NEC), a frequently fatal complication associated with premature births, in experiments involving mice. The research team, led by investigators at Johns Hopkins Children’s Center and supported by the National Institutes of Health, reports these findings advance efforts towards developing improved treatments for NEC—a condition that is relatively rare but remains the most common emergency intestinal issue among preemies.
A report on this study was published on February 13 in Cellular and Molecular Gastroenterology and Hepatology. Despite being a crucial disease that many have likely never heard of, NEC has a significant impact on premature infants and their families. The severity of the condition is exacerbated by the fact that awareness about it often comes too late, following diagnosis. Surprisingly, even healthcare professionals are sometimes unaware of what causes this condition.
By uncovering its connection with cytomegalovirus (CMV) infection, researchers have identified a vital trigger for NEC. This discovery has the potential to save the lives of premature infants who develop this condition.
NEC affects nearly 10% of premature infants. Characterized by severe inflammation of the intestinal lining that eventually kills this tissue, NEC is life-threatening for about a third of affected babies. Despite advances in medical care, survival rates have remained unchanged over the past three decades.
Prior research involving animals has shown that the hallmark inflammation associated with NEC can be partly attributed to an increased production of toll-like receptor 4 (TLR4), an immune protein activated by specific intestinal bacteria that tend to thrive in premature infants’ digestive tracts. However, why this condition is more severe in some babies and tends to spread remains a mystery.
That’s where CMV comes into play. An estimated 40% to 80% of people worldwide are chronically infected with cytomegalovirus, a virus belonging to the herpes family that usually causes no symptoms in healthy individuals but can lead to hearing loss and other organ-damaging birth defects when transmitted from mother to fetus during pregnancy.
During gestation, fetuses acquire CMV from infected mothers in 30%–50% of cases. Suspecting a connection between CMV and the severity of NEC, Hackam and his team developed a neonatal mouse model of NEC with CMV infection. By comparing the intestines of mice with and without this virus, they found that those harboring CMV experienced significantly worse tissue damage and higher mortality rates.
In their search for a molecular mechanism behind these outcomes, researchers compared gene activity in the intestines of both groups of mice. They discovered that CMV infection triggered genetic pathways promoting inflammation, disrupting metabolism, and encouraging cells to produce more TLR4. Further investigation revealed that CMV also damaged mitochondria, the cell’s energy-producing organelles.
The damage significantly reduced mitochondrial production of adenosine triphosphate (ATP), a molecule used by cells for fuel. Experiments with mouse tissue showed that TLR4 was involved in each of these effects. Mice genetically modified to produce no TLR4 in their intestines had significantly lower NEC severity even with CMV infection, suggesting that this protein could be an excellent target for developing drugs against NEC.
If animal and human studies confirm the link between CMV and NEC, another potential treatment option might involve administering adenosine, a precursor to ATP commonly sold as a dietary supplement. When researchers gave mice with both conditions adenosine, it significantly reduced the severity of NEC.
The team plans to explore these ideas in future studies. Other Johns Hopkins investigators 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 developing novel agents to inhibit TLR4 for both NEC prevention and treatment.
