A Japanese research team has identified the cell-surface receptor that allows the rubella virus to enter human cells, solving a mystery that has stood since the virus was first isolated. The protein, called nectin-4, was found to bind to the virus and to allow it to enter human airway cells and the cells of the placenta.
The team, from the Japan Institute for Health Security, Tohoku University and other institutions, published its findings in the online edition of the British science journal Nature. The discovery could help explain how rubella spreads through the air and how it causes the severe birth defects seen when a woman is infected during pregnancy.
Nectin-4 is a protein that normally helps cells stick to one another. It is already known as a receptor for the measles virus, which is a close relative of rubella in the sense that both cause childhood infections and both spread through the air. The finding that rubella uses the same doorway is a significant step in understanding the virus.
The researchers identified the protein by narrowing down a list of candidate receptors, using genetic manipulation and a harmless stand-in version of the virus, known as a pseudovirus, in human cultured cells. They confirmed that nectin-4 was present in human respiratory epithelial cells and in cells on the foetal side of the placenta.
The study, led by Yoshio Mori of the National Institute of Infectious Diseases, used a combination of proximity labelling proteomics and CRISPR gene-editing validation to identify nectin-4 as a functional entry receptor. When the researchers added nectin-4 to cells that were normally resistant to rubella, those cells became susceptible to infection. When they blocked nectin-4 or removed it genetically, infection was reduced.
The paper shows that nectin-4 interacts directly with the rubella virus’s envelope glycoprotein and helps the virus to be taken into the cell by a process called receptor-mediated endocytosis, after the virus first attaches to fats on the cell surface in a way that depends on calcium.
In laboratory models of the human airway, nectin-4 was found to allow the virus to enter cells from the side facing the body’s interior and to support the release of new virus particles from the side facing the air. That pattern provides a molecular explanation for how rubella is transmitted through the respiratory tract.
In models of the placenta, nectin-4 was found to be highly expressed on the syncytiotrophoblasts, the cells that form the main barrier between mother and foetus, and to allow infection at the maternal-foetal interface. That finding helps to explain how the virus reaches the developing baby and causes congenital rubella syndrome, the condition that can lead to deafness, blindness, heart defects and developmental problems.
The discovery does not change the advice on rubella prevention, which remains vaccination. The measles, mumps and rubella vaccine is highly effective and is the reason rubella has been eliminated in many countries. But the identification of the receptor opens new avenues for research, including a better understanding of how the virus causes disease and, potentially, new approaches to treatment.
The findings were published in Nature on 4 November, and the work has been welcomed as a long-awaited answer to a basic question about a virus that has been studied for decades. For the researchers, the next step is to explore how the discovery can be used to understand and eventually to counter the virus more effectively.
