CMV linked to increased necrotizing enterocolitis severity in premature infants

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A new study suggests that infection with cytomegalovirus (CMV), a common virus that can be transmitted from mother to fetus before birth, may significantly worsen necrotizing enterocolitis (NEC), a serious and often fatal complication of premature birth.^1,2

Led by researchers at Johns Hopkins Children’s Center and funded by the National Institutes of Health, the study sheds light on a potential factor that exacerbates NEC and could pave the way for better treatment strategies.

The impact of NEC on premature infants

“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,” said David Hackam, MD, PhD, Garrett Family Professor of Pediatric Surgery at the Johns Hopkins University School of Medicine. “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.”¹

NEC affects up to 10% of premature infants, causing severe inflammation of the intestinal lining that leads to tissue death. Despite medical advances, survival rates for NEC have remained unchanged for the past 3 decades, with about one-third of affected infants dying from the condition.¹

Investigating the CMV-NEC connection

Recent research has shown that NEC’s inflammation is partly driven by increased activity of an immune protein called toll-like receptor 4 (TLR4).³ However, the reasons why NEC severity varies and why it sometimes spreads have remained unclear.

Suspecting a connection between CMV and NEC, Hackam and his team developed a neonatal mouse model to study the effects of CMV infection on NEC severity. They found that mice infected with CMV had significantly worse intestinal tissue damage and higher mortality rates compared to those without the virus.

Further investigation revealed that CMV infection triggered genetic pathways promoting inflammation, disrupted metabolism, and increased TLR4 production. The virus also damaged mitochondria, reducing the production of adenosine triphosphate (ATP), a crucial energy molecule for cells.

Potential treatment strategies

Additional experiments suggested that targeting TLR4 could help mitigate NEC severity. In mice genetically modified to lack TLR4 in their intestines, NEC severity was significantly lower, even in the presence of CMV infection. The researchers also found that administering adenosine, a precursor to ATP, reduced NEC severity in infected mice.

These findings suggest that if the CMV-NEC connection is confirmed in human studies, potential treatment strategies could include TLR4-inhibiting drugs or adenosine supplementation to reduce disease severity.

Understanding cytomegalovirus

Cytomegalovirus is a member of the herpesvirus family and is one of the most common congenital infections worldwide. It is estimated that 40% to 80% of people worldwide carry CMV, and while the virus is generally harmless in healthy individuals, it can cause significant complications in newborns when transmitted from mother to fetus. Congenital CMV infection occurs in approximately 30% to 50% of pregnancies where the mother is infected, making it a widespread concern in maternal-fetal medicine.

Future research directions

The implications of this study extend beyond NEC. Understanding the role of CMV in disease progression could help researchers identify additional ways to support premature infants at risk of developing severe complications. Ongoing research may focus on whether antiviral therapies for CMV could be beneficial in preventing NEC or reducing its severity.

References:

1. John Hopkins Medicine. Research suggests common viral infection worsens deadly condition among premature babies. eurekalert. February 24, 2025. Accessed February 28, 2025. https://www.eurekalert.org/news-releases/1074720

2. Scheese D, Lu P, Moore H, et al. Cytomegalovirus worsens necrotizing enterocolitis severity in mice via increased Toll Like Receptor 4 signaling. Cellular and Molecular Gastroenterology and Hepatology. Published online February 2025:101473. doi:https://doi.org/10.1016/j.jcmgh.2025.101473

3. Hackam DJ, Sodhi CP. Bench to bedside - new insights into the pathogenesis of necrotizing enterocolitis. Nat Rev Gastroenterol Hepatol. 2022;19(7):468-479. doi:10.1038/s41575-022-00594-x