According to researchers, the common cold viruses are capable of infecting human placental cells and may thus transmit the infection to the fetus in the womb during pregnancy. The new study was published in the journal PLOS ONE, and provides the first concrete proof that this type of carriage is possible.
If confirmed, this would show that if a woman has a cold caused by the respiratory syncytial virus (RSV) during pregnancy, the virus can spread into fetal lung tissues and cause lung infection during intrauterine life. RSV is being shown, by many different studies, to cause not just colds and chest infection, but other remote complications, including fetal infection.
Respiratory syncytial virus (RSV), 3D illustration Credit: Kateryna Kon / Shutterstock
This theory was floated based on finding RSV antigens and genes in the circulation and peripheral tissues of infected humans. Later research showed the presence of the viral genome in toto within the lung tissues of 40% of rat babies born to pregnant rats with mid-trimester RSV infection. The virus persisted in a quarter of these rats in adulthood, even though they had been exposed only during fetal life. The genetic material from the RSV has also been found within mononuclear immune cells in cord blood in human babies, and in a baby born with congenital RSV infection because of maternal infection during the final part of the pregnancy.
The placenta is a marvellous organ with multiple functions directed towards sustaining and guarding the pregnancy, as well as terminating it when the time is appropriate. It has many different zones, some cells producing hormones while others provide nutrition to the developing pregnancy. It also acts as a physical and immunological barrier to disease-causing agents. However, recent studies show that some viruses do slip through the net.
For instance, Zika viruses do infiltrate the fetus via the placenta in early pregnancy. So do others like the cytomegalovirus (CMV), coxsackie viruses, and hepatitis B virus. This is because of their tropism, or special affinity for, certain placental cell types, using which they enter fetal tissues. Zika is attracted to Hofbauer cells and the placental fibroblasts, and the former cell type forms a natural reservoir for viral replication as well as allowing the virus to spread into the blood.
Using placentas donated by mothers who had delivered by elective Cesarean sections after a full-term uneventful pregnancy, the scientists looked at the three major types of cell found in this tissue. These comprise the cytotrophoblast cells, the fibroblasts of the placental stroma, and the Hofbauer cells. These cells were allowed to come in contact with the respiratory syncytial virus (RSV), which is responsible for the common cold.
Within the cytotrophoblast cells, viral replication was limited. However, it was able to infect the other two types of placental cell. Over 20% of fibroblast cells were infected within 96 hours. Viral infection did not kill the cells, however. Instead, especially with respect to Hofbauer cells, they not only survived the infection for up to 30 days, and allowed viral replication, but migrated to different parts of the placenta. This makes them unwitting carriers of the virus within this organ, which in turn may allow the virus to infiltrate fetal tissue as well.
When these infected Hofbauer cells were overlaid with epithelial cells, signs of infection appeared in the latter within 72 hours. The Hofbauer cells also expressed cytokines like TNF-alpha and IFN-gamma. Even though they did not release the replicated viruses, they passed on the infection to epithelial cells in close contact with them through intercellular pathways.
The number of placental cells showing signs of infection depend on the amount of the infectious agent. Thus, mothers with more severe or prolonged infection may have a higher risk of placental infection and, in turn, fetal infection.
In general, the cytotrophoblast doesn’t allow the virus to replicate itself completely. This tissue is noted for rather giving rise to fused cells that differentiate into the syncytiotrophoblast, which is then the main point of interaction between mother and fetus.
Hofbauer cells - the Trojan horse of RSV
Though the placenta is resistant to most viral and bacterial infections, some of these agents can bypass the pathway through alternative routes. This may include transcytosis via binding of IgG-virion complexes through the Fc receptor on the syncytiotrophoblast. Or they may infect trophoblast cells outside the chorionic villi that extend into the basement layer of the placenta. Once they reach this level, they can remodel the spiral arterioles of the decidua, and may even trigger infection of the Hofbauer cells.
RSV is known to be capable of persistent infection of macrophages, which may be the viral reservoirs. Thus, Hofbauer cells could be “the Trojan horses” of RSV, spreading it to other placental cell types like the stromal fibroblasts and beyond the placenta, into the developing fetal lungs. They also produce and secrete Th1 cytokines which can enable the transfer of the infection to bronchial epithelium by direct contact. Th1 cytokines have been linked to poor pregnancy outcomes or pregnancy complications. In this way, RSV may influence the outcomes of pregnancy via direct infection of Hofbauer cells which migrate into the fetal lungs, and produce infection of the epithelial cells there by direct contact, as well as by the release of soluble cytokines that can diffuse into fetal tissues and affect fetal development.
Researcher Giovanni Piedimonte says, “When they move into the fetus, they are like bombs packed with virus. They don't disseminate the virus around by exploding, which is the typical way, but rather transfer the virus through intercellular channels.” The RSV is thought to attack lung tissue inside the fetus, which can cause lung reactivity to change. The affected fetus may have a strong tendency to childhood asthma as a result. This hypothesis is an intriguing one, and the researchers plan to test it by a clinical study.
Respiratory syncytial virus exhibits differential tropism for distinct human placental cell types with Hofbauer cells acting as a permissive reservoir for infection. Vladimir Bokun, John J. Moore, Robert Moore, Carrie C. Smallcombe, Terri J. Harford, Fariba Rezaee, Frank Esper, and Giovanni Piedimonte. PLOS ONE. December 2, 2019. https://doi.org/10.1371/journal.pone.0225767. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225767