Middle East respiratory syndrome coronavirus infection causes: Difference between revisions

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===Tropism===
===Tropism===
* [[MERS-CoV]] has a strong [[tropism]] for the [[cilium|non-ciliated]] [[bronchial]] [[epithelium]].
* [[MERS-CoV]] has a strong [[tropism]] for the [[cilium|non-ciliated]] [[bronchial]] [[epithelium]].
* Less commonly, MERS-CoV may primarily infect cells of the GI tract or the neurological system. Also, it has been noted that the [[virus]] has the capacity to evade the [[innate immune system]] and inhibit [[interferon]] production.<ref name="Kindler-2013">{{Cite journal|last1=Kindler|first1=E.|last2=Jónsdóttir|first2=H. R.|last3=Muth|first3=D.|last4=Hamming|first4=O. J.|last5=Hartmann|first5=R.|last6=Rodriguez|first6=R.|last7=Geffers|first7=R.|last8=Fouchier|first8=R. A.|last9=Drosten|first9=C.|title=Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential|journal=MBio|volume=4|issue=1|pages=e00611–12|year=2013|doi= 10.1128/mBio.00611-12|pmid=23422412|pmc=3573664|display-authors=9}}</ref><ref name="Raj-2013">{{Cite journal|last1=Raj|first1=V. S.|last2=Mou|first2=H.|last3=Smits|first3=S. L.|last4=Dekkers|first4=D. H.|last5=Müller|first5=M. A.|last6=Dijkman|first6=R.|last7=Muth|first7=D.|last8=Demmers|first8=J. A.|last9=Zaki|first9 = A.|title=Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC|journal=Nature|volume=495|issue=7440|pages=251–4|date=March 2013|doi=10.1038/nature12005|pmid=23486063|display-authors=9}}</ref>
* Less commonly, MERS-CoV may primarily infect cells of the GI tract or the neurological system.  
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 [[cell receptor|cellular receptor]] for [[infection]], as the [[SARS-CoV]], namely the [[Angiotensin-converting enzyme 2|angiotensin converting enzyme 2]].<ref name="Perlman2013">{{cite journal|last1=Perlman|first1=S.|title=The Middle East Respiratory Syndrome--How Worried Should We Be?|journal=mBio|volume=4|issue=4|year=2013|pages=e00531-13–e00531-13|issn=2150-7511|doi=10.1128/mBio.00531-13}}</ref><ref name="RajMou2013">{{cite journal|last1=Raj|first1=V. Stalin|last2=Mou|first2=Huihui|last3=Smits|first3=Saskia L.|last4=Dekkers|first4=Dick H. W.|last5=Müller|first5=Marcel A.|last6=Dijkman|first6=Ronald|last7=Muth|first7=Doreen|last8=Demmers|first8=Jeroen A. A.|last9=Zaki|first9=Ali|last10=Fouchier|first10=Ron A. M.|last11=Thiel|first11=Volker|last12=Drosten|first12=Christian|last13=Rottier|first13=Peter J. M.|last14=Osterhaus|first14=Albert D. M. E.|last15=Bosch|first15=Berend Jan|last16=Haagmans|first16=Bart L.|title=Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC|journal=Nature|volume=495|issue=7440|year=2013|pages=251–254|issn=0028-0836|doi=10.1038/nature12005}}</ref><ref name="MullerRaj2012">{{cite journal|last1=Muller|first1=M. A.|last2=Raj|first2=V. S.|last3=Muth|first3=D.|last4=Meyer|first4=B.|last5=Kallies|first5=S.|last6=Smits|first6=S. L.|last7=Wollny|first7=R.|last8=Bestebroer|first8=T. M.|last9=Specht|first9=S.|last10=Suliman|first10=T.|last11=Zimmermann|first11=K.|last12=Binger|first12=T.|last13=Eckerle|first13=I.|last14=Tschapka|first14=M.|last15=Zaki|first15=A. M.|last16=Osterhaus|first16=A. D. M. E.|last17=Fouchier|first17=R. A. M.|last18=Haagmans|first18=B. L.|last19=Drosten|first19=C.|title=Human Coronavirus EMC Does Not Require the SARS-Coronavirus Receptor and Maintains Broad Replicative Capability in Mammalian Cell Lines|journal=mBio|volume=3|issue=6|year=2012|pages=e00515-12–e00515-12|issn=2150-7511|doi=10.1128/mBio.00515-12}}</ref>
However, the [[cell receptor|cellular receptor]] for [[MERS-CoV]] was later identified as being the ''dipeptidyl [[peptidase]] 4'' (DDP4) or ''CD26''.<ref name="Raj-2013" /> 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]].<ref name="Raj-2013" /><ref name="dpp4_receptor">{{cite web|title=Receptor for new coronavirus found|url=http://www.nature.com/news/receptor-for-new-coronavirus-found-1.12584|date=2013-03-13|accessdate=2013-03-18|publisher=nature.com}}</ref> 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 membrane|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 membrane|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.<ref name="Perlman2013">{{cite journal|last1=Perlman|first1=S.|title=The Middle East Respiratory Syndrome--How Worried Should We Be?|journal=mBio|volume=4|issue=4|year=2013|pages=e00531-13–e00531-13|issn=2150-7511|doi=10.1128/mBio.00531-13}}</ref><ref name="pmid20134095">{{cite journal| author=Imai Y, Kuba K, Ohto-Nakanishi T, Penninger JM| title=Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. | journal=Circ J | year= 2010 | volume= 74 | issue= 3 | pages= 405-10 | pmid=20134095 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20134095  }} </ref><ref name="pmid12892317">{{cite journal| author=Lambeir AM, Durinx C, Scharpé S, De Meester I| title=Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. | journal=Crit Rev Clin Lab Sci | year= 2003 | volume= 40 | issue= 3 | pages= 209-94 | pmid=12892317 | doi=10.1080/713609354 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12892317  }} </ref><ref name="pmid23677473">{{cite journal| author=Herlihy SE, Pilling D, Maharjan AS, Gomer RH| title=Dipeptidyl peptidase IV is a human and murine neutrophil chemorepellent. | journal=J Immunol | year= 2013 | volume= 190 | issue= 12 | pages= 6468-77 | pmid=23677473 | doi=10.4049/jimmunol.1202583 | pmc=PMC3756559 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23677473  }} </ref> 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:<ref name="Perlman2013">{{cite journal|last1=Perlman|first1=S.|title=The Middle East Respiratory Syndrome--How Worried Should We Be?|journal=mBio|volume=4|issue=4|year=2013|pages=e00531-13–e00531-13|issn=2150-7511|doi=10.1128/mBio.00531-13}}</ref><ref name="GiererBertram2013">{{cite journal|last1=Gierer|first1=S.|last2=Bertram|first2=S.|last3=Kaup|first3=F.|last4=Wrensch|first4=F.|last5=Heurich|first5=A.|last6=Kramer-Kuhl|first6=A.|last7=Welsch|first7=K.|last8=Winkler|first8=M.|last9=Meyer|first9=B.|last10=Drosten|first10=C.|last11=Dittmer|first11=U.|last12=von Hahn|first12=T.|last13=Simmons|first13=G.|last14=Hofmann|first14=H.|last15=Pohlmann|first15=S.|title=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=Journal of Virology|volume=87|issue=10|year=2013|pages=5502–5511|issn=0022-538X|doi=10.1128/JVI.00128-13}}</ref>
*Expose fusion [[peptide]].
*Allow fusion between [[virus]] and [[cell membrane]].
*Lead to the release of the [[viral]] [[nucleocapsid]] into [[cellular]] [[cytoplasm]].


===Transmission===
===Transmission===

Revision as of 15:10, 12 June 2015

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

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]

Causes

This negatively-stained transmission electron micrograph revealed ultrastructural morphology of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Courtesy: Public Health Image Library (PHIL), Centers for Disease Control and Prevention (CDC)[5]
This highly-magnified negatively-stained transmission electron micrograph revealed ultrastructural morphology of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Courtesy: Public Health Image Library (PHIL), Centers for Disease Control and Prevention (CDC)[6]
This thin section transmission electron micrograph revealed ultrastructural morphology of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Courtesy: Public Health Image Library (PHIL), Centers for Disease Control and Prevention (CDC)[7]
This highly-magnified transmission electron micrograph revealed the presence of numerous Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virions in this tissue culture sample. Courtesy: Public Health Image Library (PHIL), Centers for Disease Control and Prevention (CDC)[8]
This highly-magnified transmission electron micrograph revealed the presence of numerous Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virions in this tissue culture sample. Courtesy: Public Health Image Library (PHIL), Centers for Disease Control and Prevention (CDC)[9]

MERS-CoV is caused by a lineage C betacoronavirus.

Taxonomy

Betacoronavirus is an enveloped, spherical (120 nm in diameter), single-stranded, positive-strand RNA virus that belongs to the family Coronaviridae of the order Nidovirales.

Genome

The betacoronavirus contains a genome composed of 30,119 nucleotides that encodes structural and non-structural proteins. The genome is considered the largest among all RNA virus genomes, reaching 27-32 kb in size.

Protein Expression

The structural proteins expressed by the betacoronavirus include: located at the 3' end of the RNA chain are:[2][10]

All 4 structural proteins are encoded by genes located at the 3' end of the RNA chain. In addition to the 4 structural proteins, the genome encodes 5 accessory proteins involved in viral assembly and evasion of the host immune system.[11][10]

Tropism

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][12]

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

In contrast to the SARS-CoV, that in its outbreak back in 2002/2003 had adapted so much to the human population that it could no longer infect bat cells, the MERS-CoV is able to infect both animal and human cells. This fact suggests the existence of a possible bat to human transmission.[13] However, considering the low probability of every infected human having been in contact with bats, it is more likely that another animal host, common in the Arabian Peninsula such as goats or camels, was the source for the infection. This is supported by the discovery of neutralizing antibodies for MERS-CoV in all dromedary camels of Oman, as well as by the full-genome sequence of MERS-CoV from dromedaries that was revealed to be 99.9% similar with the genome of human clade B of MERS-CoV. A further study on dromedary camels from Saudi Arabia, published in December 2013, revealed the presence of MERS-CoV in 90% of the evaluated dromedary camels, suggesting that dromedary camels not only could be the main reservoir of MERS-CoV, but also the animal origin of MERS. This discoveries are of extreme relevance since they allow the definition of the human populations at risk, so that further protective measures might be taken.[14][15][16] According to the March 2014 MERS-CoV summary update from the WHO, recent studies claim that camels serve as the primary source of the MERS-CoV infection in humans, while bats may be the ultimate reservoir of the virus. Evidence includes the frequency with which the virus has been found in camels, to which human cases have been exposed, seriological data which shows widespread transmission in camels and the similarity of the camel coronavirus to the human type.[17]

Gallery

References

  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. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 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. ↑ "http://phil.cdc.gov/phil/details.asp". External link in |title= (help)
  6. ↑ "http://phil.cdc.gov/phil/details.asp". External link in |title= (help)
  7. ↑ "http://phil.cdc.gov/phil/details.asp". External link in |title= (help)
  8. ↑ "http://phil.cdc.gov/phil/details.asp". External link in |title= (help)
  9. ↑ "http://phil.cdc.gov/phil/details.asp". External link in |title= (help)
  10. ↑ 10.0 10.1 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ Reusken, Chantal BEM; Haagmans, Bart L; Müller, Marcel A; Gutierrez, Carlos; Godeke, Gert-Jan; Meyer, Benjamin; Muth, Doreen; Raj, V Stalin; Vries, Laura Smits-De; Corman, Victor M; Drexler, Jan-Felix; Smits, Saskia L; El Tahir, Yasmin E; De Sousa, Rita; van Beek, Janko; Nowotny, Norbert; van Maanen, Kees; Hidalgo-Hermoso, Ezequiel; Bosch, Berend-Jan; Rottier, Peter; Osterhaus, Albert; Gortázar-Schmidt, Christian; Drosten, Christian; Koopmans, Marion PG (2013). "Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study". The Lancet Infectious Diseases. 13 (10): 859–866. doi:10.1016/S1473-3099(13)70164-6. ISSN 1473-3099.
  15. ↑ Hemida first=Maged G; Chu, Daniel KW; Poon, Ranawaka; Perera, Mohammad A A; Ng, Hoiyee-Y (Jul 2014). "MERS coronavirus in dromedary camel herd, Saudi Arabia". Retrieved 22 Apr 2014. The full-genome sequence of MERS-CoV from dromedaries in this study is 99.9% similar to genomes of human clade B MERS-CoV.
  16. ↑ Hemida, MG (2013). "Middle East Respiratory Syndrome (MERS) coronavirus seroprevalence in domestic livestock in Saudi Arabia, 2010 to 2013". Euro Surveillance. 18 (50).
  17. ↑ "Middle East respiratory syndrome coronavirus (MERS‐CoV)Summary and literature update – as of 27 March2014" (PDF). 27 Mar 2014. Retrieved 24 Apr 2014.
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 18.10 18.11 18.12 "Public Health Image Library (PHIL)".

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