The MERS CoV receptor and areas for new research….

Posted onAuthorIan M Mackay, PhD (EIC)

Middle East respiratory syndrome (MERS) is a respiratory disease of humans. The receptor for the causative coronavirus (CoV) is called dipeptidyl peptidase-4 (DPP4). DPP4 has a wide tissue distribution and a is also present in camels, horses, goats, cows, sheep, pigs and bats among others. DPP-4 in humans is found in high levels in alveolar cells, found low in the lower respiratory tract; an area in which MERS-CoV is active.[1]

Interestingly, DPP4 expression can be affected by a few things – some of which may be interesting for further study.

DPP-4 expression is upregulated in the lower respiratory tract of those with poor lung function, in the lower airways of those with untreated asthma and in its (presumably) soluble form (sDPP4) in the blood plasma of obese patients.[1-4]

Does bloodborne DPP4 interfere with MERS-CoV infection or, through perhaps reversible binding, might it contribute to systemic distribution of MERS-CoV during serious disease, carrying it aroudn the body to other organs in those with higher levels? I think these quetsions are worthy of further investigation given comorbidity plays a central role in most cases reported.

A couple of studies of DPP4 expression levels and tissue distribution in the human upper respiratory tract have not found much sign of the MERS-CoV receptor and yet upper respiratory tyract illness is not uncommon among MERS-infected patients. Is this MERS-CoV replication in the upper respiratory tract (this is my favoured hypothesis) through as yet unfound DPP4, or a remote immunologic response to a lung infection, or perhaps due to something else – a concurrent infection by a different virus?

To address this aspect, it may be useful to expand the search for DPP-4 to upper respiratory tract tissues from humans with different disease states and co-infections. I’d be especially interested to see if DPP4 receptor expression can be upregulated by viruses known to inflame the lower respiratory tract and trigger asthma exacerbations – I’m thinking about the many rhinoviruses and respiratory syncytial virus in particular.[2, 5]

MERS-CoV also seems to use sialic acids as a low-affinity but selective cellular receptor. These aid MERS-CoV attachment and entry into DPP4 positive cells.[6]

And as a PSA to my peers: this post was sparked by reading the latest literature for a review I was asked to write on MERS (yes, another one). I cannot stress enough how worthwhile it is to accept these offers to update knowledge on a topic and take the time to read. The literature moves increasingly faster but….


References…

  1. Seys LJM, Widagdo W, Verhamme FM, Kleinjan A, Janssens W, Joos GF, et al. DPP4, the MERS coronavirus receptor, is upregulated in lungs of smokers and COPD patients. Clin Infect Dis. 2017. doi: https://doi.org/10.1093/cid/cix741.
  2. Meyerholz DK, Lambertz AM, McCray PB, Jr. Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract: Implications for the Middle East Respiratory Syndrome. Am J Pathol. 2016;186(1):78-86. doi: 10.1016/j.ajpath.2015.09.014. PubMed PMID: 26597880; PubMed Central PMCID: PMCPMC4715219.
  3. Stengel A, Goebel-Stengel A, Teuffel P, Hofmann T, Busse P, Kobelt P, et al. Obese patients have higher circulating protein levels of dipeptidyl peptidase IV. Peptides. 2014;61:75-82. Epub 8/9/2014. doi: 10.1016/j.peptides.2014.09.006.
  4. Shiobara T, Chibana K, Watanabe T, Arai R, Horigane Y, Nakamura Y, et al. Dipeptidyl peptidase-4 is highly expressed in bronchial epithelial cells of untreated asthma and it increases cell proliferation along with fibronectin production in airway constitutive cells. Respir Res. 2016;17:28. doi: 10.1186/s12931-016-0342-7. PubMed PMID: 26975422; PubMed Central PMCID: PMCPMC4791890.
  5. Widagdo W, Raj VS, Schipper D, Kolijn K, van Leenders GJ, Bosch BJ, et al. Differential Expression of the Middle East Respiratory Syndrome Coronavirus Receptor in the Upper Respiratory Tracts of Humans and Dromedary Camels. J Virol. 2016;90(9):4838-42. doi: 10.1128/JVI.02994-15. PubMed PMID: 26889022; PubMed Central PMCID: PMCPMC4836314.
  6. Li W, Hulswit RJG, Widjaja I, Raj VS, McBride R, Peng W, et al. Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein. Proc Natl Acad Sci U S A. 2017. doi: 10.1073/pnas.1712592114. PubMed PMID: 28923942.