Why Some Babies Develop Serious Infections

Compared to adults, newborns are very susceptible to infections, and these infections can lead to serious health complications and even death. One factor known to affect infants’ susceptibility to infection is neonatal neutropenia, in which the child does not produce enough neutrophils, the immune system’s first responders. What underlies this immune deficiency, which greatly increases a newborn’s susceptibility to infection, is largely unknown, so doctors know little about how to prevent or treat it.

A new study in mice by Columbia University researchers now suggests that many cases of neonatal neutropenia may be due to suppression of the fetus’ hematopoietic stem cells, a natural maternal mechanism that protects the placenta from inflammation but can leave newborns vulnerable to infection if not turned off after birth.

Neonatal Neutropenia – the Clinical Challenge

Babies with neonatal neutropenia can develop early-onset sepsis, a life-threatening infection, in the first 72 hours of life. “Early sepsis is a major problem in infants, but it is even more dangerous in premature infants, and the mortality rate in these infants is very high,” explains first author Amélie Collins, MD, PhD, assistant professor of pediatrics and a neonatologist who treats these infants in the hospital.

Doctors use broad-spectrum antibiotics to treat infants with early-onset sepsis, but antibiotics are not always enough and often lead to further complications. Treatment that boosts the immune system of these infants could have a major impact. The prevailing theory on neonatal neutropenia is that fetuses and newborns with this condition lack the regenerative capacity to produce large numbers of neutrophils to fight infection. But what this actually means from a mechanistic point of view was previously unknown, according to Collins.

Experiments and Results

To understand how neutropenia develops in infants, Collins and study leader Emmanuelle Passegué, PhD, alumni professor of genetics and development at the Vagelos College of Physicians and Surgeons and director of the Columbia Stem Cell Initiative at Columbia University, used mouse models to study how fetal and neonatal hematopoietic stem cells respond to infection. Adults typically rely on emergency myelopoiesis, a rapid hematopoietic stem cell response mechanism that generates large numbers of immune cells, including neutrophils, during infections. Collins and Passegué found that although emergency myelopoiesis functions early in fetal development – fetal hematopoietic stem cells are capable of generating neutrophils – the fetus does not turn it on.

This suggests that an external factor suppresses fetal myelopoiesis. The researchers then searched for and found a maternal factor – interleukin 10 or IL-10 – that prevents emergency myelopoiesis from being activated during fetal development. Collins and Passegué found that the absence of IL-10 can restore emergency myelopoiesis in the fetus and boost neonatal neutrophil production in a way that is likely to have important clinical benefits. Now that the researchers know that fetal and neonatal stem cells can produce neutrophils, and they have identified IL-10 as one of the factors that suppresses emergency myelopoiesis, they should be able to understand that mechanism and find places where they can intervene.

Potential Implications and Future Directions

The discovery was also made possible by a second mouse model developed by the researchers, which allowed them to track what happens in the mouse pups after they are born (since removal of IL-10 in infected pregnant mice is associated with fetal death). This second model showed that newborn pups can activate emergency myelopoiesis signaling pathways after birth, which will be crucial for future studies. “We are now in a position to learn more about how maternal IL-10 suppresses fetal hematopoietic stem cells and what signaling releases the inhibitions after birth in order to translate these exciting findings into an effective therapy,” says Passegué.