Summary: New research reveals that fetuses can mount immune responses against infections long before birth, challenging the assumption that they rely solely on maternal immunity. A study on Zika virus infections found that immune cells like microglia protect the developing brain, while others, like monocytes, can cause damaging inflammation.
Researchers demonstrated that targeting harmful inflammation with an experimental drug can safeguard the fetal brain. This breakthrough opens new avenues for treating infections during pregnancy and preventing congenital disorders.
Key Facts:
- Fetal Immunity: Fetuses have a functional immune system capable of combating infections early in development.
- Protective vs. Harmful: Microglia protect the brain, but monocytes can cause inflammation that damages fetal neurons.
- Therapeutic Potential: Blocking harmful inflammatory responses with experimental drugs could prevent brain damage caused by infections.
Source: Duke NUS
The latest research from Duke-NUS Medical School has revealed that fetuses are not as defenseless as once thought; they can actually fight infections from within the womb.
This new understanding could significantly change the way doctors protect fetuses 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 fetus 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 fetus. This breakthrough discovery could potentially benefit women who contract infections during pregnancy.
Congenital disorders, including those caused by diseases transmitted from mothers to fetuses during pregnancy, cause approximately 240,000 newborn deaths yearly.
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 fetus 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 fetus’ own immune system is already able to mount defenses against infections much earlier than previously thought.”
Investigating further, the scientists studied the fetal 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 fetus’ developing brain or harming the fetus’ 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 infection and are crucial to the fetal immune system’s defense 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 fetal 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), which caused neuron damage when combined with reactive oxygen species in large volumes.
Just as bleach can damage the fibers of a piece of clothing when used in excess, so too can immune responses harm a fetus’ 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 fetuses can be either protective or harmful. Knowing how various immune cells contribute to fetal 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 fetuses 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.
About this neurodevelopment research news
Author: Brandon Raeburn
Source: Duke NUS
Contact: Brandon Raeburn – Duke NUS
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Differential contributions of fetal mononuclear phagocytes to Zika virus neuroinvasion versus neuroprotection during congenital infection” by Ashley St John et al. Cell
Abstract
Differential contributions of fetal mononuclear phagocytes to Zika virus neuroinvasion versus neuroprotection during congenital infection
Fetal immune cell functions during congenital infections are poorly understood. Zika virus (ZIKV) can vertically transmit from mother to fetus, causing nervous system infection and congenital ZIKV syndrome (CZS).
We identified differential functional roles for fetal monocyte/macrophage cell types and microglia in ZIKV dissemination versus clearance using mouse models.
Trafficking of ZIKV-infected primitive macrophages from the yolk sac allowed initial fetal virus inoculation, while recruited monocytes promoted non-productive neuroinflammation.
Conversely, brain-resident differentiated microglia were protective, limiting infection and neuronal death. Single-cell RNA sequencing identified transcriptional profiles linked to the protective versus detrimental contributions of mononuclear phagocyte subsets.
In human brain organoids, microglia also promoted neuroprotective transcriptional changes and infection clearance. Thus, microglia are protective before birth, contrasting with the disease-enhancing roles of primitive macrophages and monocytes.
Differential modulation of myeloid cell phenotypes by genetically divergent ZIKVs underscores the potential of immune cells to regulate diverse outcomes during fetal infections.
