MERS-CoV
The emergence of MERS-CoV
During the summer of 2012, in Jeddah, Saudi Arabia, an at the time unknown coronavirus was isolated from a patient with acute pneumonia and renal failure. At 2013, the Coronavirus Study Group officially named this novel coronavirus as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) [1]. As of today, the World Health Organization (WHO) has been notified of 2,254 laboratory-confirmed cases of infection with MERS-CoV in 27 countries. More than 80% of these cases have been reported in Saudi Arabia. Cases identified outside the Middle East are usually travelers who were infected in the Middle East and then travelled to areas outside of it. Out of the 2,254 reported cases, 800 of them have been fatal, making the official mortality rate approximately 35%. The combination of everything stated above, has led WHO to characterize MERS-CoV as one of the viruses most likely to cause an epidemic[2].
Transmission
MERS-CoV is a zoonotic virus, which means that it is a virus that is transmitted between animals and people. It has been proved that humans are infected through direct or indirect contact with infected dromedary camels. The origins of the virus are, at this point, not fully understood but, according to the analysis of different virus genomes, it is believed that it could have originated in bats and afterwards transmitted to camels in the distant past. The virus can also be transmitted from human-to-human, when there is close contact, such as when healthcare staff provide unprotected care to infected patients. That is the reason why there have been clusters of cases in healthcare facilities, especially when infection prevention and control practices are not followed. Thankfully, as of now, human-to-human transmission has been limited. It has only been identified among family members, patients and health care workers. So far, no sustained human to human transmission has been documented anywhere in the world [2].
Symptoms and Complications
Most people that have been infected with MERS-CoV, have been reported to have had severe acute respiratory illness with symptoms of fever, cough and shortness of breath. There have also been patients that had gastrointestinal symptoms including diarrhea, nausea and vomiting. For a substantial number of patients, more severe complications followed, such as pneumonia and kidney failure. About 35% of the reported cases have proven fatal. Most of the people who died, also suffered from one or more underlying medical conditions, like diabetes, cancer, chronic lung, heart or kidney diseases. Some infected people had mild symptoms, very similar to the ones of a common cold, making the identification of the virus difficult. There have also been cases that were reported as asymptomatic [3]. Those facts make the virus extremely dangerous, since it can be transmitted from one person to another without being noticed, making the existence of quick and accurate diagnostic methods extremely important.
Based on information that are available as of now, the incubation period for MERS (the time between the exposure to MERS-CoV and the appearance of the symptoms) is usually 5 or 6 days, but can possibly range from 2 to 14 days [3].
The virus
MERS-CoV is the first betacoronavirus lineage C member that has been found and isolated from humans. Its genome structure is a single-stranded RNA (ssRNA) and encodes 10 proteins:
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two replicase polyproteins (open reading frames (ORF) 1a and 1b),
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three structural proteins, namely an envelope small membrane protein (E), a nucleoprotein (N) that encapsulates the viral RNA and a membrane protein (M),
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a surface spike glycoprotein (S) and
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five nonstructural proteins (ORF 3, 4a, 4b, 5 and 8b) [4, 6].
Concerning the way that MERS-CoV invades its host, it is believed that Dipeptidyl peptidase 4 (DPP4 or CD26), which is present on the surfaces of human non-ciliated bronchial epithelial cells, acts as a functional receptor that enables the invasion[5]. MERS-CoV binds to DPP4 on the host cell through the spike glycoprotein, which leads to the fusion of the virus and the cell membrane, before the release of the viral RNA into the host cell cytoplasm. Initially ORF1a and ORF1b are translated into polyproteins and cleaved by the virus-encoded proteases into mature nonstructural proteins. The genomic or subgenomic RNA is replicated and encapsidated in the nucleoproteins in the cytoplasm and then transported to the Endoplasmic Reticulum–Golgi intermediate compartment (ERGIC) for further assembly. The spike, membrane and envelope proteins are also inserted into the ERGIC to interact with the nucleoprotein-encapsidated RNA and assemble into viral particles. The budded vesicles containing mature viral particles are then transported to the cell surface for release after maturation in the Golgi bodies. A fraction of the RNA that is generated via viral replication, is double-stranded RNAs (dsRNAs), and can be detected by the host, thus leading to an immune response. The 4a competes with the host’s receptors to bind to dsRNAs, effectively enabling the virus evade the host immune response [6].
Diagnosis
According to the centers for disease control and infection (CDC), in general, there are two categories of diagnosis:
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Molecular tests, which diagnose active MERS-CoV infections. Molecular testing requires real-time reverse-transcription polymerase chain reaction (rRT-PCR) assays in order to detect viral RNA in clinical samples. It is important to note that rRT-PCR testing, despite being generally reliable, is affected by a variety of factors, namely the experience and expertise of the laboratory personnel, the condition that the instrument, as well as the specimen are in and in general requires a well organized laboratory environment. Coupled with the fact that it is a costly technique, it is prominent that there is great need for the development of alternative diagnostic methods [2].
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Serology tests, which detect antibodies to MERS-CoV, thus providing evidence that the patient has been infected in the past. CDC has a two-phase approach for serology testing, which includes two screening tests and one confirmatory test to detect antibodies to MERS-CoV. Enzyme-linked immunosorbent assay (ELISA) is used to detect the presence and concentration of specific antibodies against two different MERS-CoV proteins, the nucleoprotein and spike. If a clinical sample is determined to be antibody-positive by either ELISA, then, the microneutralization test is used to confirm whether the results are indeed positive. Serology tests are suitable only for surveillance or investigational purposes and not for diagnostic ones [2].
Treatment
As of today, there is no specific antiviral treatment recommended for MERS-CoV infection. Patients with MERS often receive medical care to help relieve symptoms. For severe cases, treatment includes care to support vital organ functions [2].
Travel medicine
Travel medicine or emporiatrics is the branch of medicine that deals with the preventing and managing of health issues of people travelling around the globe[7]. Possibly the most important reason why travel medicine came to be, is the prevention of spreading diseases that were originally endemic to certain areas. Diseases such as malaria, which were spread to a limited number of counties have caused chaos in the past, after being spread internationally [8]. Although many of those diseases have been successfully dealt with, the danger of spreading new diseases worldwide is still alarming. MERS-CoV, despite being a virus, falls in the same category as malaria and if spread, it could become an immense threat to pubic health, possibly causing an epidemic, as the World Health Organization has already suggested[2].
Knowing that, combined with the fact that there is still no treatment for MERS-CoV infections, it is apparent that there is great need for potent, fast and on-site diagnosis. rRT-PCR, the most common way of detecting MERS-CoV infections, is not compatible with travel medicine, as it needs special equipment and expertise, which are not available in airports or anywhere outside modern molecular biology laboratories[2]. One the other hand, the toehold-switch diagnostic kit is portable, reliable and can be used in points of care in airports, or by any individual, as it does not require any expertise, making it immensely more usable for travel medicine.
References
[2] “Middle East Respiratory Syndrome Coronavirus (MERS-CoV).” World Health Organization, World Health Organization, 8 Oct. 2018, www.who.int/emergencies/mers-cov/en/.
[3] “Middle East Respiratory Syndrome (MERS).” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 13 July 2016, www.cdc.gov/coronavirus/mers/index.html.
[4] Kim, Y.-J., Cho, Y.-J., Kim, D.-W., Yang, J.-S., Kim, H., Park, S., … Kim, S. S. (2015). Complete Genome Sequence of Middle East Respiratory Syndrome Coronavirus KOR/KNIH/002_05_2015, Isolated in South Korea. Genome Announcements, 3(4): e00787–15.
[5] Lu, G., et al. (2013). "Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26." Nature 500: 227.
[6] Durai, P., et al. (2015). "Middle East respiratory syndrome coronavirus: transmission, virology and therapeutic targeting to aid in outbreak control." Experimental &Amp; Molecular Medicine 47: e181.
[7] David R. Hill, Charles D. Ericsson, Richard D. Pearson, Jay S. Keystone, David O. Freedman, Phyllis E. Kozarsky, Herbert L. DuPont, Frank J. Bia, Philip R. Fischer, Edward T. Ryan; The Practice of Travel Medicine: Guidelines by the Infectious Diseases Society of America, Clinical Infectious Diseases, Volume 43, Issue 12, 15 December 2006, Pages 1499–1539.
[8] “World Malaria Report 2014.” World Health Organization, World Health Organization, 30 Oct. 2015, www.who.int/malaria/publications/world_malaria_report_2014/en/.
