Middle East respiratory syndrome coronavirus infection causes

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MERS-CoV
MERS-CoV particles as seen by negative stain electron microscopy. Virions contain characteristic club-like projections emanating from the viral membrane.
MERS-CoV particles as seen by negative stain electron microscopy. Virions contain characteristic club-like projections emanating from the viral membrane.
Virus classification
Group: Group IV ((+)ssRNA)
Order: Nidovirales
Family: Coronaviridae
Subfamily: Coronavirinae
Genus: Betacoronavirus
Species: MERS-CoV

Overview

Ten years after the outbreak of SARS-CoV, the MERS-CoV is identified as the agent of a lethal pneumonia in patients who have recently been related to the Arabian Peninsula. The Middle east respiratory syndrome coronavirus (MERS-CoV), also termed EMC/2012 (HCoV-EMC/2012), is positive-sense, single-stranded RNA novel species of the genus Betacoronavirus.[1][2] First called novel coronavirus 2012 or simply novel coronavirus, it was first reported in 2012 after genome sequencing of the virus, isolated from sputum samples of patients, affected by a 2012 outbreak of a "new flu". Until May 2013, MERS-CoV was being described as a SARS-like virus or colloquially as "Saudi SARS. Since then it is known to be distinct, not only from SARS-CoV, but also from other known endemic coronaviruses, such as betacoronavirus HCoV-OC43 and HCoV-HKU1, as well as from the common cold coronavirus.[3] As of May 2014, several MERS-CoV cases have been reported in different countries, including Saudi Arabia, Malaysia, Jordan, Qatar, Egypt, the United Arab Emirates, Tunisia, Kuwait, Oman, Algeria, Bangladesh, the United Kingdom and the United States.[4]

Virology

The Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging type of coronavirus, specifically a betacoronavirus of the lineage C. The MERS-CoV is a single stranded, positive sense virus, whose genome contains 30.119 nucleotides and encodes for structural and nonstructural proteins. The structural proteins located at the 3' end of the RNA chain are also seen in the genome of other coronaviruses and may include:[2][5]

Within the genome of these 4 proteins are located RNA sequences that encode for 5 accessory proteins, exclusive of MERS-CoV and that have no homology with other host proteins. Some of these have the purpose to facilitate the viral assembly or in evading the immune system.[6][5]

Origin

The first reported case of a human infected by MERS-CoV was in September 2012, in Saudi Arabia. This patient developed a lethal infection marked by a severe pneumonia and renal failure. However, some reports claim that the infection might have occurred first in a family from Jordan in April 2012. The virus was first isolated by an egyptian physician, while he was examining the lungs of a previously unknown MERS-CoV infected patient. The isolated infected cells showed cytopathic effect with syncytia formation and noted rounding.[7][8][9][10]

In September 2012, a second case was reported in a 49 year old man in Qatar. This patient presented with flu-like symptoms and the viral sequence was proved to be similar to the one from the first case. In November of the same year, identical cases kept appearing in Saudi Arabia and Qatar, with associated deaths.

Up until now it hasn't been determined if the infections were the result of a zoonotic event, with further human-to-human transmission or if they were a case of multiple zoonotic events from a common source. A study from the Riyadh University has suggested that, since the the virus first appeared, there may have been 7 different zoonotic transmissions. Although there are still limited data, it has been noted that the coronavirus has a large genetic diversity among animal reservoirs, yet the sample analysis of the infected patients suggests a common genome and therefore source. Since this early period, several clusters of infection have been created, suggesting that a human-to-human transmission has occurred.[2]

Molecular clock analysis studies have determined that the viruses from the EMC/2012 and from England/Qatar/2012 date from 2011. This suggests, not only a single zoonotic event as source of the reported cases, possibly implying that the MERS-CoV has been present asymptomatically in the human population for longer than one year without being detected, but also that it might have suffered an independent transmission from an unidentified source.[11][12]

Tropism

Studies have shown that in humans, unlike most viruses that tend to infect ciliated cells, MERS-CoV has a strong tropism for the nonciliated bronchial epithelium. Also, it has been noted that the virus has the capacity to evade the innate immune system and inhibit interferon production.[13][14]

It took only 6 months for the MERS-CoV receptor to be identified and published. Initially, due to the similarityies between the MERS-CoV and the SARS-CoV, it was proposed that the MERS-CoV would use the same cellular receptor for infection, as the SARS-CoV, namely the angiotensin converting enzyme 2.[2][15][16] However, the cellular receptor for MERS-CoV was later identified as being the dipeptidyl peptidase 4 (DDP4) or CD26.[14] The DPP4 receptor is an ectopeptidase, which is similar to other molecules that other coronaviruses use to infect cells, such as the human angiotensin-converting enzyme 2, for SARS-CoV, and the aminopeptidade N, for alphacoronaviruses. The amino acid sequence of this receptor is a highly conserved sequence across species, being expressed in human bronchial epithelium and kidneys, and its enzymatic activity is not required for the process of infection.[14][17] When comparing the receptor for MERS-CoV with the one for SARS-CoV, it is important to notice that both are shed of the cell surface after the respective infections. In the case of SARS-CoV, the loss of this receptor leads to the worsening of the condition, evolving to a more severe pulmonary disease. On the other hand, DDP4 is a neutrophil chemorepellent and its loss from the cell surface leads to cellular changes that may alter the composition of the immune cell infiltrate, which may consequently alter the evolution of the infectious state.[2][18][19][20] After the binding of MERS-CoV to its cellular receptor, a serious of actions, similar to ones from other coronaviruses and involving host proteases, such as cathepsin B, are triggered. These include the excision of the surface glycoprotein, which will ultimately:[2][21]

Transmission

Since may 29th 2013, the WHO has warned that the MERS-CoV should be considered a "threat to the entire world".[2] Transmission of MERS-CoV is prone to occur in immunocompromised patients, or in patients with other comorbidities, such as diabetes or renal failure.[2] In a study of 23 patients of the largest outbreak so far, in Saudi Arabia, was determined that 74% had underlying diabetes mellitus, 52% renal disease and 43% lung disease, highlighting the impact of underlying comorbidities in the overall risk of infection with MERS-CoV. This evidence is further supported by the fact that cases of infected family members and health-care workers was only reported in 1 to 2% of contacts.[2][22]

At the present time it is not known the stage at which an infected MERS-CoV patient becomes contagious, if he is able to transmit the virus while there is still no evidence respiratory illness, or if there is transmission only after symptom onset. If the first is correct, then the the control of a larger outbreak will be more challenging, considering the prevalence of global traveling nowadays.[2]

One of the major gaps of knowledge about this virus is that its prevalence in the community is not known, therefore, and since most of the identified cases were patients with underlying comorbidities, there is a possibility of MERS-CoV to be a common infection in Saudi-Arabia, with which patients without these comorbidties only develop minor respiratory symptoms or are asymptomatic.[2]

Natural reservoir

Taxonomy

MERS-CoV is more closely related to the bat coronaviruses HKU4 and HKU5 (lineage 2C) than it is to SARS-CoV (lineage 2B) (2, 9), sharing more than 90% sequence identity with their closest relationships, bat coronaviruses HKU4 and HKU5 and therefore considered to belong to the same species by the International Committee on Taxonomy of Viruses (ICTV).

› Viruses
› ssRNA viruses
› Group: IV; positive-sense, single-stranded RNA viruses
› Order: Nidovirales
› Family: Coronaviridae
› Subfamily: Coronavirinae
› Genus: Betacoronavirus[24]
› Species: Betacoronavirus 1 (commonly called Human coronavirus OC43), Human coronavirus HKU1, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus, Tylonycteris bat coronavirus HKU4, MERS-CoV

Strains:

  • Isolate:
  • Isolate:
  • NCBI

Microbiology

The virus grows readily on Vero cells and LLC-MK2 cells.[29]

Corona Map

There are a number of mapping efforts focused on tracking MERS coronavirus. On 2 May 2014, the Corona Map was launched to track the MERS coronavirus in realtime on the world map. The data is officially reported by WHO or the Ministry of Health of the respective country.[30] HealthMap also tracks case reports with inclusion of news and social media as data sources as part of HealthMap MERS.

See also

References

  1. ↑ 1.0 1.1 De Groot RJ; et al. (15 May 2013). "Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Announcement of the Coronavirus Study Group". Journal of Virology. 87 (14): 7790–2. doi:10.1128/JVI.01244-13. PMC 3700179. PMID 23678167.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Perlman, S. (2013). "The Middle East Respiratory Syndrome--How Worried Should We Be?". mBio. 4 (4): e00531–13–e00531–13. doi:10.1128/mBio.00531-13. ISSN 2150-7511.
  3. ↑ Saey, Tina Hesman (27 February 2013). "Scientists race to understand deadly new virus: SARS-like infection causes severe illness, but may not spread quickly". Science News. 183 (6). p. 5.
  4. ↑ "Patient with deadly MERS virus waited hours in Florida ER". 2014-05-14. Retrieved 2014-05-14.
  5. ↑ 5.0 5.1 van Boheemen, S.; de Graaf, M.; Lauber, C.; Bestebroer, T. M.; Raj, V. S.; Zaki, A. M.; Osterhaus, A. D. M. E.; Haagmans, B. L.; Gorbalenya, A. E.; Snijder, E. J.; Fouchier, R. A. M. (2012). "Genomic Characterization of a Newly Discovered Coronavirus Associated with Acute Respiratory Distress Syndrome in Humans". mBio. 3 (6): e00473–12–e00473–12. doi:10.1128/mBio.00473-12. ISSN 2150-7511.
  6. ↑ Narayanan, Krishna; Huang, Cheng; Makino, Shinji (2008). "SARS coronavirus accessory proteins". Virus Research. 133 (1): 113–121. doi:10.1016/j.virusres.2007.10.009. ISSN 0168-1702.
  7. ↑ "ECDC Rapid Risk Assessment - Severe respiratory disease associated with a novel coronavirus" (PDF). 19 Feb 2013. Retrieved 22 Apr 2014.
  8. ↑ Ali Mohamed Zaki; Sander van Boheemen; Theo M. Bestebroer; Albert D.M.E. Osterhaus; Ron A.M. Fouchier (8 November 2012). "Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia" (PDF). New England Journal of Medicine. 367 (19): 1814. doi:10.1056/NEJMoa1211721.
  9. ↑ Falco, Miriam (24 September 2012). "New SARS-like virus poses medical mystery". CNN. Retrieved 27 September 2012.
  10. ↑ Zaki, Ali M.; van Boheemen, Sander; Bestebroer, Theo M.; Osterhaus, Albert D.M.E.; Fouchier, Ron A.M. (2012). "Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia". New England Journal of Medicine. 367 (19): 1814–1820. doi:10.1056/NEJMoa1211721. ISSN 0028-4793.
  11. ↑ "Full-Genome Deep Sequencing and Phylogenetic Analysis of Novel Human Betacoronavirus - Vol. 19 No. 5 - May 2013 - CDC". Emerging Infectious Diseases. 2013-05-19. Retrieved 2013-06-01.
  12. ↑ Lau SK, Lee P, Tsang AK, Yip CC, Tse H, Lee RA, Molecular epidemiology of human coronavirus OC43 reveals evolution of different genotypes over time and recent emergence of a novel genotype due to natural recombination. J Virol. 2011;85:11325–37. DOIExtract
  13. ↑ Kindler, E.; Jónsdóttir, H. R.; Muth, D.; Hamming, O. J.; Hartmann, R.; Rodriguez, R.; Geffers, R.; Fouchier, R. A.; Drosten, C. (2013). "Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential". MBio. 4 (1): e00611–12. doi:10.1128/mBio.00611-12. PMC 3573664. PMID 23422412.
  14. ↑ 14.0 14.1 14.2 Raj, V. S.; Mou, H.; Smits, S. L.; Dekkers, D. H.; Müller, M. A.; Dijkman, R.; Muth, D.; Demmers, J. A.; Zaki, A. (March 2013). "Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC". Nature. 495 (7440): 251–4. doi:10.1038/nature12005. PMID 23486063.
  15. ↑ Raj, V. Stalin; Mou, Huihui; Smits, Saskia L.; Dekkers, Dick H. W.; Müller, Marcel A.; Dijkman, Ronald; Muth, Doreen; Demmers, Jeroen A. A.; Zaki, Ali; Fouchier, Ron A. M.; Thiel, Volker; Drosten, Christian; Rottier, Peter J. M.; Osterhaus, Albert D. M. E.; Bosch, Berend Jan; Haagmans, Bart L. (2013). "Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC". Nature. 495 (7440): 251–254. doi:10.1038/nature12005. ISSN 0028-0836.
  16. ↑ Muller, M. A.; Raj, V. S.; Muth, D.; Meyer, B.; Kallies, S.; Smits, S. L.; Wollny, R.; Bestebroer, T. M.; Specht, S.; Suliman, T.; Zimmermann, K.; Binger, T.; Eckerle, I.; Tschapka, M.; Zaki, A. M.; Osterhaus, A. D. M. E.; Fouchier, R. A. M.; Haagmans, B. L.; Drosten, C. (2012). "Human Coronavirus EMC Does Not Require the SARS-Coronavirus Receptor and Maintains Broad Replicative Capability in Mammalian Cell Lines". mBio. 3 (6): e00515–12–e00515–12. doi:10.1128/mBio.00515-12. ISSN 2150-7511.
  17. ↑ "Receptor for new coronavirus found". nature.com. 2013-03-13. Retrieved 2013-03-18.
  18. ↑ Imai Y, Kuba K, Ohto-Nakanishi T, Penninger JM (2010). "Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis". Circ J. 74 (3): 405–10. PMID 20134095.
  19. ↑ Lambeir AM, Durinx C, Scharpé S, De Meester I (2003). "Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV". Crit Rev Clin Lab Sci. 40 (3): 209–94. doi:10.1080/713609354. PMID 12892317.
  20. ↑ Herlihy SE, Pilling D, Maharjan AS, Gomer RH (2013). "Dipeptidyl peptidase IV is a human and murine neutrophil chemorepellent". J Immunol. 190 (12): 6468–77. doi:10.4049/jimmunol.1202583. PMC 3756559. PMID 23677473.
  21. ↑ Gierer, S.; Bertram, S.; Kaup, F.; Wrensch, F.; Heurich, A.; Kramer-Kuhl, A.; Welsch, K.; Winkler, M.; Meyer, B.; Drosten, C.; Dittmer, U.; von Hahn, T.; Simmons, G.; Hofmann, H.; Pohlmann, S. (2013). "The Spike Protein of the Emerging Betacoronavirus EMC Uses a Novel Coronavirus Receptor for Entry, Can Be Activated by TMPRSS2, and Is Targeted by Neutralizing Antibodies". Journal of Virology. 87 (10): 5502–5511. doi:10.1128/JVI.00128-13. ISSN 0022-538X.
  22. ↑ Assiri, Abdullah; McGeer, Allison; Perl, Trish M.; Price, Connie S.; Al Rabeeah, Abdullah A.; Cummings, Derek A.T.; Alabdullatif, Zaki N.; Assad, Maher; Almulhim, Abdulmohsen; Makhdoom, Hatem; Madani, Hossam; Alhakeem, Rafat; Al-Tawfiq, Jaffar A.; Cotten, Matthew; Watson, Simon J.; Kellam, Paul; Zumla, Alimuddin I.; Memish, Ziad A. (2013). "Hospital Outbreak of Middle East Respiratory Syndrome Coronavirus". New England Journal of Medicine. 369 (5): 407–416. doi:10.1056/NEJMoa1306742. ISSN 0028-4793.
  23. ↑ Roos, Robert (25 September 2013). UK agency picks name for new coronavirus isolate (Report). University of Minnesota, Minneapolis, MN: Center for Infectious Disease Research & Policy (CIDRAP).
  24. ↑ 24.0 24.1 24.2 Bermingham, A.; Chand, MA.; Brown, CS.; Aarons, E.; Tong, C.; Langrish, C.; Hoschler, K.; Brown, K.; Galiano, M. (27 September 2012). "Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012" (PDF). Euro Surveillance. 17 (40): 20290. PMID 23078800.
  25. ↑ Doucleff, Michaeleen (28 September 2012). "Holy Bat Virus! Genome Hints At Origin Of SARS-Like Virus". NPR. Retrieved 29 September 2012.
  26. ↑
  27. ↑ Augustina Annan; Heather J. Baldwin; Victor Max Corman (March 2013). "Human Betacoronavirus 2c EMC/2012–related Viruses in Bats, Ghana and Europe". Emerging Infectious Disease journal - CDC. 19 (3). Retrieved 20 March 2013.
  28. ↑ "New Coronavirus Has Many Potential Hosts, Could Pass from Animals to Humans Repeatedly". ScienceDaily. Retrieved 13 December 2012.
  29. ↑
  30. ↑ "Corona Map" (Press release). 2 May 2014.

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