Unravelling the epidemiology and pathogenesis of the novel human coronavirus MERS-CoV

Due to their inherent genetic variability viruses constitute a continuous public health threat. This is particularly the case for zoonotic viruses, which suddenly make their way into the human population coming from animal reservoirs, as well-known examples like influenza, Ebola, Hendra and SARS coronavirus (CoV) have illustrated most dramatically. In this respect coronaviruses deserve special attention by their remarkable potential to change tropism. Just 10 years after the SARS-CoV outbreak, another zoonotic human coronavirus, called MERS-CoV, has emerged. This virus arose late last year in the Middle East, where it caused severe and often lethal pneumonia. More recently the virus was diagnosed also in patients in Europe and Tunesia. The pathogen was rapidly identified by Ali Zaki and the Erasmus Medical Centre as a coronavirus (1, 2). While most human coronaviruses only elicit mild upper respiratory disease, infection by MERS-CoV causes severe lower respiratory tract infection. Though so far not spreading as efficiently, this is reminiscent of SARS-CoV, which spread very rapidly, affecting >8000 patients at a ~10% fatality rate, and with a significant impact on the global economy (3). The impact of the emerging MERS-CoV epidemic cannot be estimated at this moment. Yet, the events remind us of the early days of the SARS epidemic in terms of symptoms, severity and etiology of the disease. The appearance of different cases over a nine month time period indicates that the virus is circulating in humans or in an animal species. Most alarmingly, the virus shows human-to-human transmission, albeit yet limited (4). By further adapting over time, however, the virus may be more efficiently transmitted in the human population, possibly resulting in a widespread and global pandemic. The MERS-CoV virus is most closely related to bat coronaviruses. A bat origin, possibly combined with the existence of an intermediate animal reservoir, seems therefore likely. The zoonotic potential of coronaviruses is due to the great adaptability of their viral surface protein, the spike (S) protein, to receptor molecules of other species. Recently, applicants have identified human dipeptidyl peptidase protein 4 (DPP4), expressed in the human lung, as a functional receptor for MERS-CoV (5). In addition we found that the MERS-CoV virus was able to use the evolutionary conserved DPP4 of other animal species, notably including bats, suggesting a low barrier against cross-host transmission. Importantly, current epidemiological data indicate multiple, independent zoonotic events, strongly suggesting that the virus will persist and continue to pose a threat to human health. To combat the MERS-CoV epidemic and increase our preparedness for future novel CoV epidemics, it is essential to thoroughly understand the epidemiology, zoonotic transmission and pathogenesis of this virus. Given their key role in coronavirus transmission and pathogenesis, we will focus on the further elucidation of the virus-receptor interaction. Knowledge on the S-DPP4 receptor specificity will not only help us to identify the potential virus reservoir and intermediate host but will also enable the development of a relevant animal model to study virus pathogenesis and development of intervention strategies. A deeper understanding of the distribution of DPP4 in the respiratory and enteric tract of humans and other relevant hosts will help us understand virus pathology and epidemiology. Moreover, the S protein – in particular its S1 receptor binding subunit – is the ideal target to develop tools for rapid and differentiating CoV sero-surveillance as well as for developing prevention strategies such as a candidate vaccine. In depth studies are now needed to follow up our initial studies on the discovery of this virus and its receptor. References 1. Zaki, A. M., van Boheemen, S., Bestebroer, T. M., Osterhaus, A. D. & Fouchier, R. A. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N. Engl. J. Med. 367, 1814-1820 (2012). 2. van Boheemen, S. et al. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 3, 10.1128/mBio.00473-12 (2012). 3. Keogh-Brown, M. R. & Smith, R. D. The economic impact of SARS: how does the reality match the predictions? Health Policy 88, 110-120 (2008). 4. Source WHO. http://www.who.int.proxy.library.uu.nl/csr/don/2013_02_16/en/index.html. 5. Raj, V. R. et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature, in press.