Middle East respiratory syndrome coronavirus infection pathophysiology
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Overview
Middle East Respiratory Syndrome (MERS) is a viral respiratory illness. It is caused by an emerging coronavirus, specifically a betacoronavirus called MERS-CoV (Middle East Respiratory Syndrome Coronavirus), first discovered in 2012. Potential animal reservoirs and mechanisms of transmission of MERS-CoV to humans remain unclear. Initially a zoonotic origin for MERS-CoV was suggested due to the high genetic similarity to the coronaviruses in bats. Additionally, recent reports have also described serologic data similarities in camels and related viruses have also been identified in bats. However, future studies will have to provide additional epidemiologic data linking human MERS cases to infected animals in order to determine if a particular species is a host, a source of human infection, or both.[1][2]
Pathophysiology
The Microorganism
Middle East Respiratory Syndrome (MERS) is a viral respiratory illness caused by an emerging coronavirus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) that was previously known as human betaCoV 2c EMC/2012 (hCoV-EMC).[3][4][5] Phylogenetically, MERS-CoV belongs to the lineage C, previously known as group 2c of the genus betacoronavirus of the family coronaviridae, the largest of all the RNA viruses, with positive single-stranded RNA genomes of 26–32 kilobases.[6] The positive single-stranded RNA has a long genomic mRNA that encodes for replicase polyproteins, which are further processed into multiple nonstructural proteins. The structural proteins such as conserved spike (S), envelope (E), membrane (M), and nucleocapsid are translated from subgenomic mRNAs. The subgenomic mRNAs also encode five unique accessory proteins, designated as 3, 4a, 4b, 5, and 8b, which are found only in the same lineage of viruses.[7] SARS-CoV is another betacoronavirus with which MERS-CoV shares several similarities.
Also, it has been noted that the virus has the capacity to evade the innate immune system and inhibit interferon production.[8][9] 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.[10][11][12] However, the cellular receptor for MERS-CoV was later identified as being the dipeptidyl peptidase 4 (DDP4) or CD26.[9] 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.[9][13] 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.[10][14][15][16] 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:[10][17]
- Expose fusion peptide.
- Allow fusion between virus and cell membrane.
- Lead to the release of the viral nucleocapsid into cellular cytoplasm.
Encounter With the Microorganism
Colonization
Penetration of Antimicrobial Barrier
Spread
Mechanism of Damage
Resolution
References
- ↑ "Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do" (PDF).
- ↑ "MERS Prevention and Treatment".
- ↑ Bermingham A, Chand MA, Brown CS, Aarons E, Tong C, Langrish C; et al. (2012). "Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012". Euro Surveill. 17 (40): 20290. PMID 23078800.
- ↑ Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA (2012). "Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia". N Engl J Med. 367 (19): 1814–20. doi:10.1056/NEJMoa1211721. PMID 23075143.
- ↑ de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L; et al. (2013). "Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group". J Virol. 87 (14): 7790–2. doi:10.1128/JVI.01244-13. PMC 3700179. PMID 23678167.
- ↑ Chan JF, To KK, Tse H, Jin DY, Yuen KY (2013). "Interspecies transmission and emergence of novel viruses: lessons from bats and birds". Trends Microbiol. 21 (10): 544–55. doi:10.1016/j.tim.2013.05.005. PMID 23770275.
- ↑ van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM; et al. (2012). "Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans". MBio. 3 (6). doi:10.1128/mBio.00473-12. PMC 3509437. PMID 23170002.
- ↑ 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.
- ↑ 9.0 9.1 9.2 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.
- ↑ 10.0 10.1 10.2 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.
- ↑ 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.
- ↑ 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.
- ↑ "Receptor for new coronavirus found". nature.com. 2013-03-13. Retrieved 2013-03-18.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.