It is a situation many parents will recognize: a wayward child is throwing a tantrum in a store.

The parent takes the child by the hand to lead them out of the store, but they don’t see the toddler grab a lighter from one of the shelves on the way. They leave, no alarms sound and the parent doesn’t realize the child is now in possession of a dangerous fire starter. Now imagine the parent is a protein called nectin-1. The child is another protein called nectin-4. These proteins provide a passage between neighboring cells, and new research shows when nectin-1 pulls nectin-4 from one cell to another, sometimes what nectin-4 snatches from its cell’s cytoplasm is a virus. This finding from researchers at Mayo Clinic is a breakthrough in viral infection research, and provides insight into how the measles virus might find its way into the brain.

Measles, our Longstanding Enemy

Image of a single virus particle, or “virion”, of measles virus. Courtesy of Centers for Disease Control Public Health Image Library

As of August 27th, 2019, measles has infected 1,215 people in the United States. Before introduction of a vaccine in 1963, measles infected an estimated 3-4 million people, caused swelling in the brain (encephalitis) associated with intellectual disability or deafness in about 1,000 Americans each year, and killed an estimated 400-500, according to the Centers for Disease Control and Prevention.

In one very, very rare form of measles infection, the virus causes a disease of the central nervous system called “subacute sclerosing panencephalitis.” Although the neurological symptoms don’t appear until years after infection, researchers think that the virus gets to the brain of a patient and slowly progresses, causing memory loss, irritability, loss of motor control and in some cases seizures and loss of sight. There is no cure. And until now, researchers were unable to suggest a plausible mechanism for how measles enters brain neurons.

Now, however, a research team led by Roberto Cattaneo, Ph.D., report in the Journal of Cell Science that neuron cells were infected via the nectin-1/nectin-4 receptor complex.

To read an interview with first author Alex Generous, go to the Journal of Cell Science. To hear a podcast discussion on this work and related virology news, head over to This Week In Virology.

Roberto Cattaneo, Ph.D.

Dr. Cattaneo explained the potential significance saying that the finding may explain unaccounted aspects of infectious disease pathogenesis. “We show that when certain cells juxtapose, one rips a piece of the other off. The “acceptor” cell not only takes up a piece of the membrane of the “donor” cells, but also its cytoplasm. One virus, measles, can take advantage of this process to spread from epithelial cells to neurons,” he says.

Tracking Measles to the Brain

Normally, measles virus travels along a very specific path the body. A patient breathes in airborne particles, which infects white blood cells patrolling the lung. The virus uses the immune cells as a Trojan Horse to spread throughout the body. Eventually, it is delivered to the trachea using nectin-4, and then is breathed out into the air to spread to a new person.

 So how does measles virus reach neurons?

Dr. Cattaneo’s group tracked fluorescent measles virus moving from nectin-4 expressing epithelial cells into nectin-1 expressing neurons by the newly discovered transfer process. This is in contrast to cells expressing the protein that allows the virus to infect immune cells; they do not transfer the virus to neurons. Together, these results indicated that this transfer is specific to nectin-4 expressing cells and therefore the cytoplasm transfer process they discovered.

Image of nectin-1 (red) pulling the measles virus receptor nectin-4 (green) into the nectin-1 expressing cell. Nucleus shown in blue. Image courtesy of Alex Generous, first author on the Journal of Cell Science paper.

Next Steps on the Research Path

While this provides a plausible mechanism for neuronal entry of measles, it is not definitive. But if the researchers can extend their findings to an animal model, it may provide a pathway to drug development. According to Dr. Cattaneo, “once [the process is] mechanistically understood, the intercellular streams of cytoplasm we discovered could be harnessed for the targeted transfer of therapeutics, including oncolytics, between cells.”

Dr. Cattaneo’s group is moving forward with characterizing the exact molecular mechanism of the process, which may give hints about what makes certain patients susceptible to neuronal infection while most people never develop it.

Funding for this work and the research team was provided by National institutes of Health, Mayo Clinic Center for Biomedical Discovery, Mayo Clinic Center for Clinical and Translational Science, the Life Science Research Foundation and others.