The placenta is the bridge between the mother and fetus during pregnancy, facilitating the exchange of nutrients, oxygen, and hormones. However, parasites like Plasmodium falciparum, the culprit behind malaria, can infect the fetus through the placenta. With an estimated 231 million malaria cases and 405,000 deaths annually, understanding the placenta's defense mechanisms is essential for maternal and fetal health (1).

In a recent study, researchers from geneticist Roser Vento-Tormo’s group at the Wellcome Sanger Institute revealed a previously uncharacterized part of the placental immune system. The researchers used human placental explants and single-cell RNA sequencing (scRNA-seq) to highlight how specialized macrophages known as Hofbauer cells (HBC) help defend against different pathogens (2). Their findings uncovered new mechanisms for how the placenta combats infectious diseases, allowing for the development of new therapeutic avenues. 

“Malaria causes miscarriages, stillborn birth, and intrauterine growth restrictions,” said Elias Ruiz-Morales, a graduate student in Vento-Tormo’s laboratory and a study coauthor. “If we can modulate inflammation in the case of malaria, we can potentially reduce the number of miscarriages that we see in infected women.”

Traditionally, placental research relied on mouse models. Human placentas, unlike those in mice, are highly compartmentalized and have separate maternal and fetal zones. To overcome this limitation, the group used placental explants obtained with informed consent following Cesarian sections. These explants retained viability for up to 72 hours. “We could not have done this without the generous donation from our tissue donors,” said Ruiz-Morales. The tissue explants allowed the researchers to directly investigate how the human placenta responded to various pathogens, including those causing malaria and listeriosis. The researchers found that these pathogens activated fetal  HBC. Historically, scientists thought that HBC acted as fetal-derived macrophages that aided nutrient exchange and regulated trophoblast invasion. The role of HBC in fetal immune defense was previously unknown. 

The HBC from our placenta explants demonstrated an immune response when we exposed them to different pathogens. Targeting these inflammation pathways could lead to pregnancy-specific infection treatment, which is not currently possible. 
- Elias Ruiz-Morales, Wellcome Sanger Institute

The researchers performed scRNA-seq on placenta explants following exposure to each pathogen. P. falciparum triggered an upregulation of heme oxygenase-1 (HMOX1) within HBC. HMOX1 is an enzyme with potent anti-inflammatory and antioxidant properties, suggesting a potential role for HBC in mitigating placental oxidative stress — an indication of infection. The team saw that the bacterium Listeria monocytogenes triggered an upregulation of genes associated with the innate immune response in the placenta explants, specifically in the HBC. These HBC upregulated toll-like receptor-2, a pathogen-recognition receptor crucial for activating the innate immune response against this bacterium.

“The HBC from our placenta explants demonstrated an immune response when we exposed them to different pathogens,” said Ruiz-Morales. “Targeting these inflammation pathways could lead to pregnancy-specific infection treatment, which is not currently possible.” 

Deanne Taylor, a bioinformatician at The Children’s Hospital of Philadelphia and who was not associated with the paper added, “This study opens up new avenues into placental research and its translation to the clinic.”

The previously unknown role of HBC in placental defense will hopefully open the door to treatments for infections during pregnancy as well as a better understanding placental immunity. In the future, Vento-Tormo’s team hopes to extend placenta explants' viability for longer than 72 hours. This will be crucial for studying chronic placental conditions.

Ruiz-Morales said, “I hope that this work on the placenta can help women and children all around the world.”   

References

1. Leal Filho, W., May, J., May, M. & Nagy, G.J. Climate change and malaria: some recent trends of malaria incidence rates and average annual temperature in selected sub-Saharan African countries from 2000 to 2018. Malar J  22, 248 (2023).
2. Hoo, R. et al. Acute response to pathogens in the early human placenta at single-cell resolution. Cell Syst  15, 425-444.e9 (2024).