Why mice don't get MERS

Mouse I’m interested in Middle East Respiratory Syndrome Coronavirus (MERS-CoV) for a number of reasons, and as a result I have a student currently doing a final year project with me on this topic – not chucking buckets of MERS-CoV around in the laboratory, but trying to figure out where this virus came from and what it is likely to do next. Both of these are interesting questions.

There has been a lot published about the origins of MERS-CoV recently. Only this week came the news that a camel in Saudi Arabia has tested positive for the virus. But which came first – the virus or the camel? Almost certainly the camel – there’s no reason to suppose that camels are the original source of the outbreak. MERS is almost certainly a zoonotic infection – arising in animals and transmitted to humans – but which animals? The closest relatives to MERS-CoV have been found in bats, and those viruses are pretty similar to the virus currently causing human deaths. However, these bat viruses have only been identified by nucleotide sequences and have never been isolated as live viruses from either bats or the environment, so the animal reservoir of MERS-CoV has still not been identified (Emergence of the Middle East Respiratory Syndrome Coronavirus. (2013) PLoS Pathog 9(9): e1003595. doi:10.1371/journal.ppat.1003595).

If we don’t know where MERS came from, we should all be interested in the question of what it is likely to do next. Since September 2012, there have been over 150 laboratory-confirmed cases of infection with MERS-CoV – not that many on a global scale. That’s because the virus is only weakly infectious in humans. As long as this remains the case we are OK, but if at some point it decides it likes being in humans and wants more of the same, then we’re in trouble. What are the odds of that happening? Right now, we simply don’t know. And that’s why I’m interested in MERS.

To answer the question of what MERS will do next, we need a lot more knowledge than we have right now. One of the key pieces of information is exactly how MERS-CoV gets inside a host cell, and specifically, why it finds it difficult to infect human cells. It was recently shown that the receptor MERS-CoV needs to infect cells is dipeptidyl peptidase 4, a cell surface protein which cleaves dipeptides from hormones and chemokines after a proline amino acid residue, regulating their bioactivity (Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. (2013) Nature 495, 251-254). Dipeptidyl peptidase 4 is similar to other known coronavirus receptors, but the use of these peptidases as receptors by coronaviruses could be more related to their abundance on epithelial and endothelial tissues – the primary tissues involved in coronavirus infection – rather than any inherent properties of the protein.

That’s where a new paper in the Journal of General Virology comes in. It’s difficult to study lethal viruses in humans, so like it or not animal models of infection still have their place in these life-threatening outbreaks. The study of SARS-CoV pathogenesis progressed rapidly due to the development of a mouse adapted variant of SARS-CoV that produced lethal lung disease in mice similar to SARS in humans. But MERS-CoV doesn’t like growing in mice and it turns out that this is because mice have low levels of dipeptidyl peptidase 4 mRNA in their lungs (Wild type and innate immune deficient mice are not susceptible to the Middle East Respiratory Syndrome Coronavirus. J Gen Virol. 06 Nov 2013 doi: 10.1099/vir.0.060640-0). Good news for the mice, but also of great interest when thinking about how the pathogenesis of MERS is shaped in humans. Most viruses are not able to switch from one receptro to another easily, so drugs which interfere with the binding of the virus to this protein or antibodies which block attachment could be the best way to treat MERS until we have a vaccine which is able to stop people becoming infected. And the search for those drugs and antibodies is going on right now.

 

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