Middle East respiratory syndrome coronavirus infection pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]
Overview
MERS-CoV has a strong tropism for the non-ciliated bronchial epithelium. The virus has the capacity to evade the innate immune system and inhibit interferon production. It uses the DPP4 (or CD26) receptor to bind to the host cell and to release viral nucleocapsid into the cellular cytoplasm. Once inside the cell, viral replication follows and proteins are expressed. The viral genes encode 4 structural proteins and 5 accessory proteins.
Pathophysiology
Incubation Period
- The incubation period for MERS infection is 5–7 days, with a range of 2–14 days.[1][2]
- Immunocompromised patients can present with longer incubation periods of up to 20 days.
Cellular Pathogenesis
- The virus has the capacity to evade the innate immune system and inhibit interferon production.[3][4]
- Due to the similarities between the MERS-CoV and the SARS-CoV, it was initially proposed that the MERS-CoV possible uses the same cellular receptor for infection, as the SARS-CoV, namely the angiotensin converting enzyme 2[5][6][7], however, the cellular receptor for MERS-CoV was later identified to be dipeptidyl peptidase 4 (DDP4) or CD26.[4]
- 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.[4][8]
- DDP4 is a neutrophil chemorepellent. Its loss from the cell surface results in cellular alteration of the composition of the immune cell infiltrate and subsequent alteration of the natural history of the infectious state.[5][9][10][11]
- When MERS-CoV binds to its cellular receptor, a series of reactions involving host proteases, such as cathepsin B, are triggered. These include the excision of the surface glycoprotein, which will ultimately:[5][12]
- Expose fusion peptide
- Allow fusion between virus and cell membrane
- Lead to the release of the viral nucleocapsid into cellular cytoplasm
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:[5][13]
- 1 Nucleocapsid (N) protein is required for encapsidation and viral replication
- 1 Glycoprotein is required for viral entry into the host cell
- 2 membrane proteins required for viral structure and assembly
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.[14][13]
Tropism
- MERS-CoV has a strong tropism for the non-ciliated bronchial epithelium.
- Less commonly, MERS-CoV may primarily infect cells of the GI tract or the neurological system.
Transmission
- MERS-CoV is thought to have a zoonotic activity, whereby transmission occurs from animals to humans.
- Although bats are the natural host of the betacoronavirus, it is unknown if MERS coronavirus transmission to humans is through bats, through an intermediate animal hosts following crossover and subsequent adaptation, or through a completely different host.
- Limited data is available to confirm or rule out human-to-human transmission.
Associated Conditions
- Co-infection of MERS-CoV with other respiratory viruses such as:[15]
References
- ↑ Zumla A, Hui DS, Perlman S (September 2015). "Middle East respiratory syndrome". Lancet. 386 (9997): 995–1007. doi:10.1016/S0140-6736(15)60454-8. PMC 4721578. PMID 26049252.
- ↑ Hui DS, Azhar EI, Kim YJ, Memish ZA, Oh MD, Zumla A (August 2018). "Middle East respiratory syndrome coronavirus: risk factors and determinants of primary, household, and nosocomial transmission". Lancet Infect Dis. 18 (8): e217–e227. doi:10.1016/S1473-3099(18)30127-0. PMC 7164784 Check
|pmc=value (help). PMID 29680581. - ↑ 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.
- ↑ 4.0 4.1 4.2 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.
- ↑ 5.0 5.1 5.2 5.3 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.
- ↑ 13.0 13.1 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.
- ↑ 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.
- ↑ Arabi YM, Balkhy HH, Hayden FG, Bouchama A, Luke T, Baillie JK, Al-Omari A, Hajeer AH, Senga M, Denison MR, Nguyen-Van-Tam JS, Shindo N, Bermingham A, Chappell JD, Van Kerkhove MD, Fowler RA (February 2017). "Middle East Respiratory Syndrome". N. Engl. J. Med. 376 (6): 584–594. doi:10.1056/NEJMsr1408795. PMC 5362064. PMID 28177862.