Main component of the pathomechanism of measles identified- new insights useful for cancer treatment?

Measles remains a dangerous disease – every year, around 120,000 people still die from the consequences of measles infection worldwide. The measles virus which causes the disease is a highly contagious pathogenic agent. Non-vaccinated people contract the disease with a probability of more than 90 per cent if they come into contact with an individual who has the disease. Even though measles are considered eradicated in large parts of the world thanks to extensive vaccination campaigns, local outbreaks of the disease continue to occur in Germany. 780 cases were reported to the Robert Koch-Institut in 2010.

Intriguingly, the course of the pathomechanism has so far not been fully understood in detail. A few years ago, scientists identified the pathway by which the virus enters the body: Naturally occurring wild-type measles viruses apparently infect primarily macrophages and dendritic cells in the airways via a specific receptor – the signalling lymphocyte-activation molecule (SLAM). These infected cells find their way through local lymph nodes to then invade the lymphatic organs where extensive replication takes place. The route which the pathogenic agents finally use to return to the airways and then exit the body, however, has so far been poorly understood. In a joint collaboration with research groups from the USA, Canada, Singapore, and France, Dr Michael Mühlebach and colleagues from the Medical Biotechnology Division of the Paul-Ehrlich-Institut have now found an explanation for this mystery. "We specifically searched for a protein which is situated on the basal surface of epithelial cells and is thus accessible for the virus, and enables its access into the epithelial cell", explained Mühlebach. For their investigation, the scientists made use of as many as seven different cell lines from lung and bladder tumours, some of them infectable by wild type measles viruses, others not. The scientists compared the expressed messenger RNA, i.e. they examined which proteins are specifically present in the infectable group of cells. From the group of candidate proteins which only the infectable cell lines had in common, the scientists selected those twelve proteins that showed the strongest expression levels, as well as 18 other proteins which were potential candidates owing to their individual characteristics. The individual candidate proteins were expressed in cell lines which measles viruses can normally not enter, because these cells lack a protein which allows viral entry. Then, the scientists analysed whether the cells became infectable in the presence of one of the respective candidate receptor proteins. That way, they identified the transmembrane protein Nectin-4, which confers susceptibility to measles infection. Nectin-4 is a protein of the immunoglobulin super family and is also known as poliovirus-receptor-related-4 (PVRL4). To provide evidence that Nectin-4 is actually essential for measles infection, Mühlebach and colleagues specifically blocked Nectin-4 gene expression in infectable cell lines and were able to prevent the virus from entering the treated cells, in accordance with Nectin-4´s role as a virus receptor on cells.

However, the scientists did not want to leave it at that, since tumour cell lines may also express proteins which are barely found in the respective healthy cells. The scientists therefore also analysed the relevance of Nectin-4 in 'normal' human airway epithelial cells which were cultivated in an epithelial layer comparable to that in the airways. The expression of Nectin-4 messenger RNA was also corroborated here. Likewise, the infection by measles viruses could be prevented by a specific blockade of Nectin-4 gene expression by so-called 'small interfering RNAs' (siRNAs). These and further experiments suggest that the epithelial cell receptor Nectin-4 takes a key position in the route by which the virus exits its host via the airways.

Possible implications for cancer research

The findings by Mühlebach and colleagues may also become significant for cancer treatment. Measles viruses are already used as oncolytic viruses: They induce tumour cell death by replicating in these cells. It has so far been difficult, however, to predict their efficiency against individual tumours or in patients. Nectin-4 is produced in elevated amounts not only in carcinomas derived from epithelial cells of the airways or the bladder, but frequently also in breast cancer, intestine cancer, or other tumours of epithelial origin. "Now, there is the intriguing question of whether the efficiency of the tumour cell infection possibly correlates with the level of Nectin-4 expression, or whether a prognosis about the efficacy of treatment with Nectin-4 dependent oncolytic virus is possible before the start of the treatment", explained Professor Klaus Cichutek, the president of the Paul-Ehrlich-Institut, who is also a co-author of the publication.

Further Information

Mühlebach MD, Mateo M, Sinn PL, Prüfer S, Uhlig KM, Leonard VHJ, Navaratnarajah CK, Frenzke M, Wong XX, Sawatsky B, Ramachandran S, McCray Jr PB, Cichutek K, von Messling V, Lopez M, Cattaneo R (2011): Adherens junction protein nectin-4 (PVRL4) is the epithelial receptor for measles virus.
Nature 480: 530-533.
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DOI: 10.1038/nature10639

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