Revisiting the origins of contagion - the measles story

The mechanisms behind the incredible infectiousness of measles are poorly understood - that is, until now, where two studies have now come forward investigating the molecular biology of measles person-person transmission. Two groups have independently identified the protein, nectin-4 (a cell adhesion molecule) as the receptor allowing measles to infect and emerge from the respiratory tract and spread from person to person, potentially filling in a major gap in our understanding of this important human pathogen.

The measles virus is one of - if not the most - infectious agents currently circulating in human populations. It is also responsible for considerable disease and death worldwide, particularly across the developing world. But luckily, the introduction of a live-attenuated vaccine has significantly reduced it's incidence - this is in spite of a number of recent outbreaks associated with reduced vaccination rates. 

Owing to it's relatively easily manipulated genome, the availability of relevant infection models and a wealth of biology known about it, we can use measles as a model to understand how some respiratory viruses infect, cause disease and are transmitted from person-to-person. This is something which is extremely important for viruses which are perhaps less amenable to experimental study (for example: hendra and nipah viruses) but which share some basic biology with measles. 

A paper out this week in Nature by a group from the Mayo Clinic, reports an investigation into the mechanisms measles uses to escape from an infected person and establish a new infection - the very basis of contagion. In it, they identified the receptor molecule (nectin-4) which the virus uses to specifically infect the respiratory epithelium, providing this pathogen with an easy exit from it's host. This paper comes months after the PLoS Pathogens paper, which also identified the exact same molecule as the epithelial receptor but failed to extend this observation to more relevant models of infection, i.e. animals. I discussed the PLoS paper here.

In order to understand the complex process of infection for any microbe, we first have to know how it initially enters our body, replicates, and ultimately, leaves to infect a new host. We now know that the measles virus initially infects immune cells that reside deep inside your lungs and from here it is transferred to draining lymph nodes, providing it with ample access to it's key target cells: lymphocytes throughout the body. One thing that has not been understood is how, while now inside immune cells, the virus can hope to escape.

First phase of measles infection - immune cells

From pathological and experimental studies, we have seen that the virus can also infect epithelial cells lining the airways and from here could theoretically be shed into respiratory secretions and transmitted via coughs and sneezes etc. The problem is that we're not sure how the virus can even enter these cells as the only known receptor molecule for measles (SLAM CD150) is only found on those characteristic immune cells previously identified.  Knowledge of this specific epithelial receptor would allow us to close the gap in understanding this pathogen's life cycle, something that this Nature paper and the PLoS Pathogens one have addressed, giving us a mechanism to explain an already known phenomenon.

  

The Nature paper compared gene expression data from a range of cell lines that allow for measles replication with those that did not. This allowed them to narrow down the identity to a protein that was only found on measles replicating cells. Through a number of these experiments they tracked it down to a cell surface protein called nectin-4 - the very protein previously identified as the epithelial receptor. They also carry out some biochemical work, showing a specific interaction between the viral receptor binding protein and nectin-4.

To further test whether this protein was the correct one, the group performed a number of experiments in different cell lines, including well-differentiated human epithelial cells (an excellent model of respiratory tract biology) and even extended it to monkey work. In all experiments shown, nectin-4 was clearly a major player in allowing the measles virus to infect cells and in the macaque studies, measles replication was only shown to occur inside nectin-4 expressing epithelial cells lining the trachea and the lung.

What these two studies tell us is the specifics of how measles can infect epithelial cells lining the respiratory tract. The virus cannot infect these cells at the beginning of an infection probably due to the localized expression of nectin-4 on the bottom of the cells, but infects airway immune cells which transfer the virus throughout the body establishing a major infection and many of the disease symptoms. At the peak of infection, virus is most likely transferred from infected lymphocytes to airway epithelial cells allowing replication and transmission from inside the airways. One gap in this understanding is in the interactions between measles-infected lymphocytes and airway epithelial cells expressing nectin-4. Also this work does not rule out lymphocyte mediated transmission via those immune cells residing in tissues surrounding the airways.

Final phase (release) infection of nectin-4 positive cells in airways

The identification of nectin-4 as the measles receptor may explain why the virus is so good at killing some types of cancer cells, i.e those expressing nectn-4 highly. . Genetically engineered versions of the measles virus are being developed to target and eliminate specific cancers and may now be specifically targeted to those nectin-4 positive tumors.

Mühlebach, M., Mateo, M., Sinn, P., Prüfer, S., Uhlig, K., Leonard, V., Navaratnarajah, C., Frenzke, M., Wong, X., Sawatsky, B., Ramachandran, S., McCray, P., Cichutek, K., von Messling, V., Lopez, M., & Cattaneo, R. (2011). Adherens junction protein nectin-4 is the epithelial receptor for measles virus Nature DOI: 10.1038/nature10639