Closing the book on measles infection - do we know it all?

Measles infection. (http://biowiki.org)

One of most important factors in establishing a viral infection is the presence or absence of particular receptor molecules. These proteins/sugar molecules (or whatever) must be expressed on the surface of the cell, allowing the virus to bind and initiate entry. 

The expression of a receptor therefore governs the behavior of an infection by allowing only certain cells to permit virus replication. This thus controls how a virus enters your body, spreads throughout it, causes disease and finally escapes to continue the infection in a new host. The identity of the receptor that a virus uses allows a better understanding of infection and pathogenesis and may facilitate the development of new antiviral treatments.

A paper published in PLoS Pathogens (see here), this week documents the discovery that a protein - Nectin-4 - acts as the receptor that may allow measles virus (MeV) to escape your body in the ends-stages of the disease, through the infection of the epithelial cells lining your respiratory tract. However, this molecule differs from that used bythe virus to initially enter your body.

This Nectin-4 study finally sheds light on what has been an elusive molecule to find and goes a long way in explaining the basic biology of this historic human pathogen. Also, the findings that Nectin-4 is highly expressed on the surface of a number of common cancers further adds weight to the use of MeV as an anti-cancer agent. But does Nectin-4 fully explain MeV infection? And, can we finally close the book on measles infection?

Despite the widespread use of a highly effective - and safe - vaccine, MeV still infects an estimated 20 million people a year, mostly young children and, in 2008, the WHO documented that measles caused the death of 164,000 of these children that year. Measles is characterised by fever, photophobia, cough, runny nose, sickness, and a nasty rash over most of the body (see picture above). Every so often the virus will enter your brain and can cause serious inflammation there. And, even more rarely will the virus persist in your body only to re-emerge years later as an incurable degenerative brain disease known as sub-acute sclerosing pan-encephalitis (SSPE). The molecular basis of how this virus enters our body, replicates, spreads inside you exits your body are only now being realised with modern recombinant viruses, like those expressing fluorescent proteins (see below). For examples, see here, here, here and here. 

Disclaimer: these references are from work that my supervisor and the group I am currently in are heavily involved in but are the only work documenting MeV in the entire organism. Read here when I previously wrote about the discovery of how MeV enters our body through dendritic cells.

GFP-expressing MeV infection in a Rhesus macaque model - many organs afflicted and recapitulates human disease. Virus replication in, A) Outer skin, corresponding to rash, B) oral mucosa, C) tongue and tonsil, D) lymph node, E) Lung, F) stomach and intestine (gut-associated lymphoid tissue - GALT), G) intestine and spleen, H) and I) both close-up of 'koplik spot' skin rash. (de Swart, et al 2007)

It was always assumed that following breathing in virus-laden aerosols MeV initially infected your epithelial cells lining the upper respiratory tract. From here it could spread throughout your body, replicating in lymphocytes and finally be released back out via the epithelial cells. But, researchers using a green-fluorescent protein (GFP)-expressing MeV showed that it was in fact dendritic cells (sentinal immune cells) found within your respiratory tract that were the first cells to be infected. These cells could then easily transmit the virus to your immune cells. These cell types can be justified through the identify of the receptor for measles, SLAM that is only expressed on these immune cells. 

GFP-expressing MeV infection of A) polarised epithelial cells, B) and C) lymphoid like cells in mucosa. (de Swart et al, 2007)

However, based on animal models and autopsy reports, we know that the virus can - and does - productively infect epithelial cells lining your airway (see figure above) yet no receptor was known. That is, until Chris Richardson's team at Dalhousie University, Canada discovered that Nectin-4 could function as a MeV epithelial receptor. 

PVRL4 (Nectin-4) allows MeV infection

The group used microarray analysis to determine what genes were expressed in cells that could, and those that could not, be infected by a wild-type, pathogenic MeV. 

They were then able to bioinformatically pull out proteins that were found on the plasma membrane surface (ones that were likely to be receptors) and expressed them in cells that couldn't be infected. The gene that allowed MeV to infect was the receptor molecule and this was confirmed to be Nectin-4 through siRNA knockdown and antibody binding assays.

So does Nectin-4 explain how MeV infects, causes disease and escapes the human body? Based on the Human Protein Atlas entry for Nectin-4, this protein is on most normal cells weakly - including the brain and lung, which are both targets for MeV and it is not really expressed on lymphoid cells, although these cells already express a highly-active receptor for the virus. This study may explain how the virus can infect your respiratory tract epithelium and be secreted into your airways to spread the infection. The role of Nectin-4 should be established in further model systems like the macaque and even in vitro differentiated epithelial cells.

de Swart RL, Ludlow M, de Witte L, Yanagi Y, van Amerongen G, McQuaid S, Yüksel S, Geijtenbeek TB, Duprex WP, & Osterhaus AD (2007). Predominant infection of CD150+ lymphocytes and dendritic cells during measles virus infection of macaques. PLoS pathogens, 3 (11) PMID: 18020706 


Lemon K, de Vries RD, Mesman AW, McQuaid S, van Amerongen G, Yüksel S, Ludlow M, Rennick LJ, Kuiken T, Rima BK, Geijtenbeek TB, Osterhaus AD, Duprex WP, & de Swart RL (2011). Early target cells of measles virus after aerosol infection of non-human primates. PLoS pathogens, 7 (1) PMID: 21304593

Noyce, R., Bondre, D., Ha, M., Lin, L., Sisson, G., Tsao, M., & Richardson, C. (2011). Tumor Cell Marker PVRL4 (Nectin 4) Is an Epithelial Cell Receptor for Measles Virus PLoS Pathogens, 7 (8) DOI: 10.1371/journal.ppat.1002240