Fetal defense: Duke-NUS study reveals early immune protection in the womb

• Duke-NUS researchers have discovered that foetuses can manage their own immune responses to combat diseases and infections like Zika
• The study found that a new drug could reduce harmful inflammation in the foetal brain during congenital infections, offering new approaches to protect foetuses’ brain health
• The finding could have implications for the care of pregnant women who are infected with Zika virus as well as other common diseases affecting pregnancy including rubella, cytomegalovirus infection and toxoplasmosis

Singapore, 9 December 2024—Latest research from Duke-NUS Medical School has revealed that foetuses are not as defenceless as once thought; they can actually fight infections from within the womb. This new understanding could significantly change the way doctors protect foetuses from infections that lead to serious health conditions, like microcephaly, where the baby’s head is significantly smaller than expected for its age.

In the study, published in the journal Cell, the researchers discovered that a foetus has a functional immune system that is well-equipped to combat infections in its developing nervous system, long before birth. It had previously been shown that the mother’s immune system was the sole source of protection from infection for a foetus. This breakthrough discovery could potentially benefit women who contract infections during pregnancy. Congenital disorders, including those caused by diseases transmitted from mothers to foetuses during pregnancy, cause approximately 240,000 newborn deaths yearly[1].

Associate Professor Ashley St John from the Programme in Emerging Infectious Diseases at Duke-NUS, the lead author on the study, said:

“Early in pregnancy, a foetus cannot survive on its own and we have always assumed that it mostly relies on the mother’s immune system for protection against infections. However, we found that the foetus’ own immune system is already able to mount defences against infections much earlier than previously thought.”

Investigating further, the scientists studied the foetal immune response in a preclinical model using Zika virus strains from around the world. They found that immune cells react differently to infection—either taking on a protective role and reducing damage to the foetus’ developing brain or harming the foetus’ brain by causing non-protective inflammation.

The study revealed new insights into the role of microglia, a type of immune cell found in the brain. Using human brain models known as organoids or mini-brains, the researchers confirmed that these cells take on a protective role during an infection and are crucial to the foetal immune system’s defence against pathogens.

Monocytes, white blood cells produced in the bone marrow, were another type of immune cell that the researchers studied. The team, which included A*STAR scientists, found that besides being drawn to the foetal brain during an infection, they triggered detrimental inflammation in the brain, killing brain cells instead of eliminating the virus. While it had previously been shown that monocytes’ harmful nature only manifests after birth, this finding showed that these immune cells can also cause damage to a developing foetal brain before birth.

Additionally, monocytes produce highly reactive molecules known as reactive oxygen species that help the body combat pathogens by alerting cells to a pathogen, a state in which they release inflammatory signals. However, the researchers observed an increased release of a particular inflammatory signal, called nitric oxide synthase-2 (NOS2), caused neuron damage when combined with reactive oxygen species in large volumes. Just as bleach can damage the fibres of a piece of clothing when used in excess, so too can immune responses harm a foetus’ brain if they are not properly regulated.    

In response to this finding, the scientists used an experimental anti-inflammatory drug to block the function of NOS2. This led to the reduction of non-protective inflammation induced by monocytes in the brain and protected the foetal brain from the damage that Zika infections can cause.

Assoc Prof St John said that the study brings a fresh perspective to the fight against congenital disorders stemming from infections:

“Our work has shown that the immune responses of foetuses can be either protective or harmful. Knowing how various immune cells contribute to foetal immune protection will be important in our continued search for ways to improve pregnancy outcomes.”

“We hope that with further testing, we can establish the safety of the anti-inflammatory drug so that it can be developed into a viable form of treatment that protects foetuses from harmful inflammation in their brains,” she added.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, commented:

“Around the world, there are huge efforts underway to map the different cells in our bodies and how they contribute to human health and disease. By revealing the intricacies of our earliest immune responses, this study brings us a step closer to having a more comprehensive understanding of the human body’s inner workings, potentially paving the way for new medical interventions.”  

This new research is part of Duke-NUS’ efforts to improve global health by bringing together basic scientific research and translational applications to pioneer novel biomedical solutions.

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DOI: https://doi.org/10.1016/j.cell.2024.10.028

About Duke-NUS Medical School

Duke-NUS is Singapore’s flagship graduate entry medical school, established in 2005 with a strategic, government-led partnership between two world-class institutions: Duke University School of Medicine and the National University of Singapore (NUS). Through an innovative curriculum, students at Duke-NUS are nurtured to become multi-faceted ‘Clinicians Plus’ poised to steer the healthcare and biomedical ecosystem in Singapore and beyond. A leader in ground-breaking research and translational innovation, Duke-NUS has gained international renown through its five Signature Research Programmes and ten Centres. The enduring impact of its discoveries is amplified by its successful Academic Medicine partnership with Singapore Health Services (SingHealth), Singapore’s largest healthcare group. This strategic alliance has led to the creation of 15 Academic Clinical Programmes, which harness multi-disciplinary research and education to transform medicine and improve lives.   

For more information, please visit www.duke-nus.edu.sg 
 

For media enquiries, please contact:

Brandon Raeburn
Communications
Duke-NUS Medical School
Tel: +65 9776 8496
Email: braeburn@duke-nus.edu.sg

[1] This is based on a 2023 World Health Organisation report on the number of deaths caused by congenital disorders within 28 days of birth.: https://www.who.int/news-room/fact-sheets/detail/birth-defects