Down the slope: links between infection during pregnancy and brain development
When things go wrong early on in brain development, they start a snowball effect, which only gets bigger and bigger as the brain matures. This has the potential of causing brain disorders later in life.
The snowball effect is a phenomenon that describes something that begins small, then increasingly becomes larger and more complex, until its origins are hard to pinpoint and often lost in translation. This analogy could be applicable to development in the womb, beginning from a handful of microscopic cell interactions, a full organism with incredible complexity then emerges. Similarly, this also describes the diseases that may acquire an unwanted “head start” as organs, like the brain, are just beginning to form.
It is well known that developmental brain disorders like autism and schizophrenia have different causes. On one hand, environmental exposures to toxins, infections or injuries can increase the risk of developing these disorders. Alternatively, developmental abnormalities can be inherited from the parents, coded in their genetic material. The exact points of origin of these disorders may not always be clear. However, scientists try to gain clues regarding the origin of disease using experimental models that look at snapshots of different developmental stages, for example, before or after birth.
The harmful consequences of alcohol and tobacco use during pregnancy are frequently warned, but infections can also have very harmful effects. “It is very well established that viral infections like rubella, cytomegalovirus, Zika and West Nile viruses; as well as parasite infections like toxoplasmosis, lead to an immune response in pregnant women that can cause diseases in the offspring”, said Kelly Baines, one of the scientists in Dr. Stephen Renaud’s team at Western University. Due to the changes in the heart, lungs and immune system during pregnancy, even common infections like the flu may cause severe illness in pregnant women, and be harmful to the developing fetus.
Using a rodent model, Dr. Renaud’s team studied how activating the immune defenses of a pregnant animal would affect the development of the progeny before birth. It was already known that when this maternal immune response is activated, which occurs during any infection, the offspring present behavioural changes such as cognitive deficits. While other studies in the field have focused on what happens to the offspring after birth, but there were still many questions about the immediate effects of this immune activation inside the womb. The Renaud Lab and their collaborators published an article in Frontiers in Immunology this past June focusing on the early effects of maternal immune activation on the developing rat embryo.
Baines, a Ph.D. Candidate in the Renaud Lab, stressed that abundant research has made it clear that it is not the kind of infection the mother contracts during pregnancy that harms the baby’s brain development, but rather the response to the infection from the mother’s immune system. When we get a cold or a sore throat, the infection that is attacking us would commonly be a virus or bacteria. These microorganisms are very different and use alternative strategies to make us sick. However, the body’s way of fighting these microorganisms are similar. For example, symptoms like fever, which are part of the body’s response to infection, could be present in both viral and bacterial infections.
To activate the pregnant animal’s immune system, Baines used a compound that looks like the components of a virus, or something a virus-infected cell would produce, but it’s not a real virus. “This way, the maternal immune system responds as if there was an infection, without any additional negative symptoms like those seen during a real infection”, she explained. The treated animals do not get sick, but the defenses are activated, and the embryos are affected.
First, the researchers treated the pregnant animal with the immune-activating compound and a few hours after, collected embryonic samples. “The samples we took allowed us to look simultaneously at the effects in the pregnant animal and the embryo”, Baines explained. In their analysis, Baines and her colleagues found that the pregnant rat produces a strong immune response, and that the immune activating compound changes the embryonic chemical signals that coordinate brain development.
The Western researchers then continued to follow the growing snowball a little further down the slope, by looking at the developing embryonic brain a week after immune activation. Dr. Renaud’s group found that particular regions of the brain were bigger compared to embryos where the maternal immune response was not activated. Bigger is not always better, especially during brain development; a balance between the number of cells and how they connect is key for a healthy outcome.
But what exactly was making the brain bigger? Looking deeper at these abnormal brains, the Renaud Lab identified the specific cell type responsible for this difference in size: neuronal precursors cells (NPCs). NPCs can multiply to make more brain cells and help the brain grow in size.
Brain development is a highly coordinated process. Cells come in, do their job and then leave or die to make room for the next participants. In Baines’ animal model, they found more NPCs than expected in embryos that had been exposed to immune activation, and these cells appeared to be behaving abnormally. This could explain the differences in sizes found in the brains of the embryos. Baines noted that this change in brain size and abnormal NPCs fit with other studies that follow the offspring after birth. Baines added, “We found these alterations in NPCs during brain development, but the consequences after birth will require further research.”
Having identified the cells that are involved in the first stage of the snowball, research can now try to identify how to redirect these cells back into order. The Renaud lab found that a protein called Notch, could be further studied as a target for potential therapeutic applications. “Notch dysregulation caused by maternal immune activation fits very well with the alterations we observed in the effected embryos, and is an exciting research to follow up on”, said Baines. Improving our understanding this activation will provide more clues on how to correct or compensate the negative effects.
Although researchers understand what a diseased brain looks like, they cannot find the cause of what has gone awry. They can see the giant snowball, getting bigger and more complex, but they don’t know where the snowball started. Developmental research like that done in the Renaud lab tries to find early ways to stop the avalanche, starting with the snowballs, with the hopes of yielding results that help us prevent brain disorders.
Original article: Baines KJ, Hillier DM, Haddad FL, Rajakumar N, Schmid S and Renaud SJ (2020) Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats. Front. Immunol. 11:1145. doi: 10.3389/fimmu.2020.01145 https://www.frontiersin.org/articles/10.3389/fimmu.2020.01145/full