Host determinants of mers-CoV transmission and pathogenesis

Viruses

Volumn 11, Issue 3, 2019, Pages

  Widagdo, W ^a   Na Ayudhya, Syriam Sooksawasdi ^a   Hundie, Gadissa B ^a   Haagmans, Bart L ^a  

^a ERASMUS MEDICAL CENTER   (Netherlands)

Author keywords

DPP4; Host factors; MERS CoV; Pathogenesis; Transmission

Indexed keywords

CARCINOEMBRYONIC ANTIGEN RELATED CELL ADHESION MOLECULE 1; DIPEPTIDYL PEPTIDASE IV; GLUCOSE REGULATED PROTEIN 78; HOST FACTOR; INTERFERON; SERINE PROTEINASE; SIALIC ACID; VIRUS RNA;

ANTIVIRAL ACTIVITY; BRONCHUS EPITHELIUM; CAMEL; CLINICAL OUTCOME; DROMEDARY; ENZYME ACTIVITY; HUMAN; IMMUNOCOMPROMISED PATIENT; INNATE IMMUNITY; LUNG ALVEOLUS CELL; LUNG ALVEOLUS EPITHELIUM; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; MIXED INFECTION; NONHUMAN; NOSE EPITHELIUM; PNEUMONIA; PROTEIN EXPRESSION; REVIEW; RISK FACTOR; T CELL DEPLETION; TRACHEA EPITHELIUM; UPPER RESPIRATORY TRACT INFECTION; VACCINATION; VIRUS CELL INTERACTION; VIRUS CHARACTERIZATION; VIRUS INFECTION; VIRUS PATHOGENESIS; VIRUS REPLICATION; VIRUS TRANSMISSION; ANIMAL; BAT; CORONAVIRUS INFECTION; HOST PATHOGEN INTERACTION; METABOLISM; PATHOGENICITY; PHYSIOLOGY; RESPIRATORY TRACT INFECTION; VIRAL TROPISM; VIROLOGY;

ANIMALS; CAMELUS; CHIROPTERA; CORONAVIRUS INFECTIONS; DIPEPTIDYL PEPTIDASE 4; HOST-PATHOGEN INTERACTIONS; HUMANS; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; RESPIRATORY TRACT INFECTIONS; VIRAL TROPISM; VIRUS REPLICATION;

EID: 85063613281     PISSN: None     EISSN: 19994915     Source Type: Journal    
DOI: 10.3390/v11030280     Document Type: Review

References (129)

1. Zaki, A.M.; van Boheemen, S.; Bestebroer, T.M.; Osterhaus, A.D.; Fouchier, R.A. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N. Engl. J. Med. 2012, 367, 1814–1820.
2. World Health Organization MERS Situation Update, March 2018. Available online: http://www.emro.who.int/pandemic-epidemic-diseases/mers-cov/mers-situation-update-march-2018.htm l (accessed on 1 March 2019).
3. Widagdo, W.; Okba, N.M.A.; Stalin Raj, V.; Haagmans, B.L. MERS-coronavirus: From discovery to intervention. One Health 2017, 3, 11–16.
4. The WHO Mers-CoV Research Group. State of Knowledge and Data Gaps of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Humans. PLoS Curr. 2013, 5, doi:10.1371/currents.outbreaks.0bf719e352e7478f8ad85fa30127ddb8.
5. Moon, S.Y.; Son, J.S. Infectivity of an Asymptomatic Patient With Middle East Respiratory Syndrome Coronavirus Infection. Clin. Infect. Dis. 2017, 64, 1457–1458.
6. Memish, Z.A.; Al-Tawfiq, J.A.; Makhdoom, H.Q.; Al-Rabeeah, A.A.; Assiri, A.; Alhakeem, R.F.; AlRabiah, F.A.; Al Hajjar, S.; Albarrak, A.; Flemban, H.; et al. Screening for Middle East respiratory syndrome coronavirus infection in hospital patients and their healthcare worker and family contacts: A prospective descriptive study. Clin. Microbiol. Infect. 2014, 20, 469–474.
7. Drosten, C.; Meyer, B.; Muller, M.A.; Corman, V.M.; Al-Masri, M.; Hossain, R.; Madani, H.; Sieberg, A.; Bosch, B.J.; Lattwein, E.; et al. Transmission of MERS-coronavirus in household contacts. N. Engl. J. Med. 2014, 371, 828–835.
8. Kim, S.W.; Park, J.W.; Jung, H.D.; Yang, J.S.; Park, Y.S.; Lee, C.; Kim, K.M.; Lee, K.J.; Kwon, D.; Hur, Y.J.; et al. Risk factors for transmission of Middle East respiratory syndrome coronavirus infection during the 2015 outbreak in South Korea. Clin. Infect. Dis. 2017, 64, 551–557.
9. Normile, D. South Korea finally MERS-free. Science 2015, doi:10.1126/science.aae0157.
10. World Health Organization Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Republic of Korea—Disease Outbreak News 25 October 2015. Available online: http://www.who.int/csr/don/25-october-2015-mers-korea/en/(1 March 2019).
11. World Health Organization MERS-CoV Global Summary and Assessment of Risk. July 2017. Available online: http://www.who.int/emergencies/mers-cov/risk-assessment-july-2017.pdf?ua=1 (1 March 2019).
12. Dudas, G.; Carvalho, L.M.; Rambaut, A.; Bedford, T. MERS-CoV spillover at the camel-human interface. Elife 2018, 7, eLife.31257.
13. Haagmans, B.L.; Al Dhahiry, S.H.; Reusken, C.B.; Raj, V.S.; Galiano, M.; Myers, R.; Godeke, G.J.; Jonges, M.; Farag, E.; Diab, A.; et al. Middle East respiratory syndrome coronavirus in dromedary camels: An outbreak investigation. Lancet Infect. Dis. 2014, 14, 140–145.
14. Memish, Z.A.; Cotten, M.; Meyer, B.; Watson, S.J.; Alsahafi, A.J.; Al Rabeeah, A.A.; Corman, V.M.; Sieberg, A.; Makhdoom, H.Q.; Assiri, A.; et al. Human infection with MERS coronavirus after exposure to infected camels, Saudi Arabia, 2013. Emerg. Infect. Dis. 2014, 20, 1012–1015.
15. Paden, C.R.; Yusof, M.; Al Hammadi, Z.M.; Queen, K.; Tao, Y.; Eltahir, Y.M.; Elsayed, E.A.; Marzoug, B.A.; Bensalah, O.K.A.; Khalafalla, A.I.; et al. Zoonotic origin and transmission of Middle East respiratory syndrome coronavirus in the UAE. Zoonoses. Public Health 2018, 65, 322–333.
16. Briese, T.; Mishra, N.; Jain, K.; Zalmout, I.S.; Jabado, O.J.; Karesh, W.B.; Daszak, P.; Mohammed, O.B.; Alagaili, A.N.; Lipkin, W.I. Middle East respiratory syndrome coronavirus quasispecies that include homologues of human isolates revealed through whole-genome analysis and virus cultured from dromedary camels in Saudi Arabia. MBio 2014, 5, e01146-14.
17. Haagmans, B.L.; van den Brand, J.M.; Raj, V.S.; Volz, A.; Wohlsein, P.; Smits, S.L.; Schipper, D.; Bestebroer, T.M.; Okba, N.; Fux, R.; et al. An orthopoxvirus-based vaccine reduces virus excretion after MERS-CoV infection in dromedary camels. Science 2016, 351, 77–81.
18. Adney, D.R.; van Doremalen, N.; Brown, V.R.; Bushmaker, T.; Scott, D.; de Wit, E.; Bowen, R.A.; Munster, V.J. Replication and shedding of MERS-CoV in upper respiratory tract of inoculated dromedary camels. Emerg. Infect. Dis. 2014, 20, 1999–2005.
19. Meyer, B.; Muller, M.A.; Corman, V.M.; Reusken, C.B.; Ritz, D.; Godeke, G.J.; Lattwein, E.; Kallies, S.; Siemens, A.; van Beek, J.; et al. Antibodies against MERS coronavirus in dromedary camels, United Arab Emirates, 2003 and 2013. Emerg. Infect. Dis. 2014, 20, 552–559.
20. Muller, M.A.; Corman, V.M.; Jores, J.; Meyer, B.; Younan, M.; Liljander, A.; Bosch, B.J.; Lattwein, E.; Hilali, M.; Musa, B.E.; et al. MERS coronavirus neutralizing antibodies in camels, Eastern Africa, 1983-1997. Emerg. Infect. Dis. 2014, 20, 2093–2095.
21. Reusken, C.B.; Messadi, L.; Feyisa, A.; Ularamu, H.; Godeke, G.J.; Danmarwa, A.; Dawo, F.; Jemli, M.; Melaku, S.; Shamaki, D.; et al. Geographic distribution of MERS coronavirus among dromedary camels, Africa. Emerg. Infect. Dis. 2014, 20, 1370–1374.
22. Alagaili, A.N.; Briese, T.; Mishra, N.; Kapoor, V.; Sameroff, S.C.; Burbelo, P.D.; de Wit, E.; Munster, V.J.; Hensley, L.E.; Zalmout, I.S.; et al. Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia. MBio 2014, 5, e00884-14.
23. Raj, V.S.; Mou, H.; Smits, S.L.; Dekkers, D.H.; Muller, M.A.; Dijkman, R.; Muth, D.; Demmers, J.A.; Zaki, A.; Fouchier, R.A.; et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013, 495, 251–254.
24. Li, W.; Hulswit, R.J.G.; Widjaja, I.; Raj, V.S.; McBride, R.; Peng, W.; Widagdo, W.; Tortorici, M.A.; van Dieren, B.; Lang, Y.; et al. Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein. Proc. Natl. Acad. Sci. USA 2017, 114, E8508–E8517.
25. de Wilde, A.H.; Raj, V.S.; Oudshoorn, D.; Bestebroer, T.M.; van Nieuwkoop, S.; Limpens, R.W.; Posthuma, C.C.; van der Meer, Y.; Barcena, M.; Haagmans, B.L.; et al. MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-alpha treatment. J. Gen. Virol. 2013, 94 Pt 8, 1749–1760.
26. Iwata-Yoshikawa, N.; Okamura, T.; Shimizu, Y.; Hasegawa, H.; Takeda, M.; Nagata, N. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J. Virol. 2019, doi:10.1128/JVI.01815-18.
27. Fehr, A.R.; Perlman, S. Coronaviruses: An overview of their replication and pathogenesis. Methods. Mol. Biol. 2015, 1282, 1–23.
28. Boonacker, E.; Van Noorden, C.J. The multifunctional or moonlighting protein CD26/DPPIV. Eur. J. Cell. Biol. 2003, 82, 53–73.
29. Wang, N.; Shi, X.; Jiang, L.; Zhang, S.; Wang, D.; Tong, P.; Guo, D.; Fu, L.; Cui, Y.; Liu, X.; et al. Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Res. 2013, 23, 986– 993.
30. Lu, G.; Hu, Y.; Wang, Q.; Qi, J.; Gao, F.; Li, Y.; Zhang, Y.; Zhang, W.; Yuan, Y.; Bao, J.; et al. Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature 2013, 500, 227– 231.
31. Bosch, B.J.; Raj, V.S.; Haagmans, B.L. Spiking the MERS-coronavirus receptor. Cell Res. 2013, 23, 1069–1070.
32. de Wit, E.; Rasmussen, A.L.; Falzarano, D.; Bushmaker, T.; Feldmann, F.; Brining, D.L.; Fischer, E.R.; Martellaro, C.; Okumura, A.; Chang, J.; et al. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc. Natl. Acad. Sci. USA 2013, 110, 16598–16603.
33. Haagmans, B.L.; van den Brand, J.M.; Provacia, L.B.; Raj, V.S.; Stittelaar, K.J.; Getu, S.; de Waal, L.; Bestebroer, T.M.; van Amerongen, G.; Verjans, G.M.; et al. Asymptomatic Middle East respiratory syndrome coronavirus infection in rabbits. J. Virol. 2015, 89, 6131–6135.
34. Raj, V.S.; Smits, S.L.; Provacia, L.B.; van den Brand, J.M.; Wiersma, L.; Ouwendijk, W.J.; Bestebroer, T.M.; Spronken, M.I.; van Amerongen, G.; Rottier, P.J.; et al. Adenosine deaminase acts as a natural antagonist for dipeptidyl peptidase 4-mediated entry of the Middle East respiratory syndrome coronavirus. J. Virol. 2014, 88, 1834–1838.
35. Coleman, C.M.; Matthews, K.L.; Goicochea, L.; Frieman, M.B. Wild-type and innate immune-deficient mice are not susceptible to the Middle East respiratory syndrome coronavirus. J. Gen. Virol. 2014, 95 Pt 2, 408–412.
36. Iwata-Yoshikawa, N.; Fukushi, S.; Fukuma, A.; Suzuki, T.; Takeda, M.; Tashiro, M.; Hasegawa, H.; Nagata, N. Non Susceptibility of Neonatal and Adult Rats against the Middle East Respiratory Syndrome Coronavirus. Jpn. J. Infect. Dis. 2016, 69, 510–516.
37. Chu, H.; Chan, C.M.; Zhang, X.; Wang, Y.; Yuan, S.; Zhou, J.; Au-Yeung, R.K.; Sze, K.H.; Yang, D.; Shuai, H.; et al. Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells. J. Biol. Chem. 2018, 293, 11709–11726.
38. Chan, C.M.; Chu, H.; Wang, Y.; Wong, B.H.; Zhao, X.; Zhou, J.; Yang, D.; Leung, S.P.; Chan, J.F.; Yeung, M.L.; et al. Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 Is an Important Surface Attachment Factor That Facilitates Entry of Middle East Respiratory Syndrome Coronavirus. J. Virol. 2016, 90, 9114–9127.
39. Zheng, Y.; Shang, J.; Yang, Y.; Liu, C.; Wan, Y.; Geng, Q.; Wang, M.; Baric, R.; Li, F. Lysosomal proteases are a determinant of coronavirus tropism. J. Virol. 2018, 92, e01504.
40. Park, J.E.; Li, K.; Barlan, A.; Fehr, A.R.; Perlman, S.; McCray, P.B. Jr.; Gallagher, T. Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism. Proc. Natl. Acad. Sci. USA 2016, 113, 12262–12267.
41. Shirato, K.; Kawase, M.; Matsuyama, S. Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. J. Virol. 2013, 87, 12552–12561.
42. Millet, J.K.; Whittaker, G.R. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc. Natl. Acad. Sci. USA2014, 111, 15214–15219.
43. Earnest, J.T.; Hantak, M.P.; Li, K.; McCray, P.B. Jr.; Perlman, S.; Gallagher, T. The tetraspanin CD9 facilitates MERS-coronavirus entry by scaffolding host cell receptors and proteases. PLoS Pathog. 2017, 13, e1006546.
44. Muller, C.; Hardt, M.; Schwudke, D.; Neuman, B.W.; Pleschka, S.; Ziebuhr, J. Inhibition of Cytosolic Phospholipase A2alpha Impairs an Early Step of Coronavirus Replication in Cell Culture. J. Virol. 2018, 92, e01463-17.
45. Belov, G.A.; van Kuppeveld, F.J. (+)RNA viruses rewire cellular pathways to build replication organelles. Curr. Opin. Virol. 2012, 2, 740–747.
46. Belov, G.A.; Nair, V.; Hansen, B.T.; Hoyt, F.H.; Fischer, E.R.; Ehrenfeld, E. Complex dynamic development of poliovirus membranous replication complexes. J. Virol. 2012, 86, 302–312.
47. Rabouw, H.H.; Langereis, M.A.; Knaap, R.C.; Dalebout, T.J.; Canton, J.; Sola, I.; Enjuanes, L.; Bredenbeek, P.J.; Kikkert, M.; de Groot, R.J.; et al. Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses. PLoS Pathog. 2016, 12, e1005982.
48. Canton, J.; Fehr, A.R.; Fernandez-Delgado, R.; Gutierrez-Alvarez, F.J.; Sanchez-Aparicio, M.T.; Garcia-Sastre, A.; Perlman, S.; Enjuanes, L.; Sola, I. MERS-CoV 4b protein interferes with the NF-kappaB-dependent innate immune response during infection. PLoS Pathog. 2018, 14, e1006838.
49. Siu, K.L.; Yeung, M.L.; Kok, K.H.; Yuen, K.S.; Kew, C.; Lui, P.Y.; Chan, C.P.; Tse, H.; Woo, P.C.; Yuen, K.Y.; et al. Middle east respiratory syndrome coronavirus 4a protein is a double-stranded RNA-binding protein that suppresses PACT-induced activation of RIG-I and MDA5 in the innate antiviral response. J. Virol. 2014, 88, 4866–4876.
50. Nakagawa, K.; Narayanan, K.; Wada, M.; Popov, V.L.; Cajimat, M.; Baric, R.S.; Makino, S. The endonucleolytic RNA cleavage function of nsp1 of Middle East respiratory syndrome coronavirus promotes the production of infectious virus particles in specific human cell lines. J. Virol. 2018, 92, e01157-18.
51. Knoops, K.; Kikkert, M.; Worm, S.H.; Zevenhoven-Dobbe, J.C.; van der Meer, Y.; Koster, A.J.; Mommaas, A.M.; Snijder, E.J. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol. 2008, 6, e226.
52. Thornbrough, J.M.; Jha, B.K.; Yount, B.; Goldstein, S.A.; Li, Y.; Elliott, R.; Sims, A.C.; Baric, R.S.; Silverman, R.H.; Weiss, S.R. Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation. MBio 2016, 7, e00258-16.
53. Menachery, V.D.; Mitchell, H.D.; Cockrell, A.S.; Gralinski, L.E.; Yount, B.L. Jr.; Graham, R.L.; McAnarney, E.T.; Douglas, M.G.; Scobey, T.; Beall, A.; et al. MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis. MBio 2017, 8, e00665–17.
54. Oudshoorn, D.; Rijs, K.; Limpens, R.; Groen, K.; Koster, A.J.; Snijder, E.J.; Kikkert, M.; Barcena, M. Expression and Cleavage of Middle East Respiratory Syndrome Coronavirus nsp3-4 Polyprotein Induce the Formation of Double-Membrane Vesicles That Mimic Those Associated with Coronaviral RNA Replication. MBio 2017, 8, e01658–17.
55. Li, K.; Wohlford-Lenane, C.L.; Channappanavar, R.; Park, J.E.; Earnest, J.T.; Bair, T.B.; Bates, A.M.; Brogden, K.A.; Flaherty, H.A.; Gallagher, T.; et al. Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. Proc. Natl. Acad. Sci. USA 2017, 114, E3119–E3128.
56. Cockrell, A.S.; Yount, B.L.; Scobey, T.; Jensen, K.; Douglas, M.; Beall, A.; Tang, X.C.; Marasco, W.A.; Heise, M.T.; Baric, R.S. A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nat. Microbiol. 2016, 2, 16226.
57. Zhao, J.; Li, K.; Wohlford-Lenane, C.; Agnihothram, S.S.; Fett, C.; Zhao, J.; Gale, M.J. Jr.; Baric, R.S.; Enjuanes, L.; Gallagher, T.; et al. Rapid generation of a mouse model for Middle East respiratory syndrome. Proc. Natl. Acad. Sci. USA 2014, 111, 4970–4975.
58. Yao, Y.; Bao, L.; Deng, W.; Xu, L.; Li, F.; Lv, Q.; Yu, P.; Chen, T.; Xu, Y.; Zhu, H.; et al. An animal model of MERS produced by infection of rhesus macaques with MERS coronavirus. J. Infect. Dis. 2014, 209, 236–242.
59. Falzarano, D.; de Wit, E.; Martellaro, C.; Callison, J.; Munster, V.J.; Feldmann, H. Inhibition of novel beta coronavirus replication by a combination of interferon-alpha2b and ribavirin. Sci. Rep. 2013, 3, 1686.
60. Raj, V.S.; Farag, E.A.; Reusken, C.B.; Lamers, M.M.; Pas, S.D.; Voermans, J.; Smits, S.L.; Osterhaus, A.D.; Al-Mawlawi, N.; Al-Romaihi, H.E.; et al. Isolation of MERS coronavirus from a dromedary camel, Qatar, 2014. Emerg. Infect. Dis. 2014, 20, 1339–1342.
61. Cho, S.Y.; Kang, J.M.; Ha, Y.E.; Park, G.E.; Lee, J.Y.; Ko, J.H.; Lee, J.Y.; Kim, J.M.; Kang, C.I.; Jo, I.J.; et al. MERS-CoV outbreak following a single patient exposure in an emergency room in South Korea: An epidemiological outbreak study. Lancet. 2016, 388, 994–1001.
62. Chan, R.W.; Chan, M.C.; Agnihothram, S.; Chan, L.L.; Kuok, D.I.; Fong, J.H.; Guan, Y.; Poon, L.L.; Baric, R.S.; Nicholls, J.M.; et al. Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus in human ex vivo respiratory organ cultures. J. Virol. 2013, 87, 6604–6614.
63. Chan, R.W.; Hemida, M.G.; Kayali, G.; Chu, D.K.; Poon, L.L.; Alnaeem, A.; Ali, M.A.; Tao, K.P.; Ng, H.Y.; Chan, M.C.; et al. Tropism and replication of Middle East respiratory syndrome coronavirus from dromedary camels in the human respiratory tract: An in-vitro and ex-vivo study. Lancet Respir. Med. 2014, 2, 813–822.
64. Ng, D.L.; Al Hosani, F.; Keating, M.K.; Gerber, S.I.; Jones, T.L.; Metcalfe, M.G.; Tong, S.; Tao, Y.; Alami, N.N.; Haynes, L.M.; et al. Clinicopathologic, Immunohistochemical, and Ultrastructural Findings of a Fatal Case of Middle East Respiratory Syndrome Coronavirus Infection in United Arab Emirates, April 2014. Am. J. Pathol. 2016, 186, 652–658.
65. Hocke, A.C.; Becher, A.; Knepper, J.; Peter, A.; Holland, G.; Tonnies, M.; Bauer, T.T.; Schneider, P.; Neudecker, J.; Muth, D.; et al. Emerging human middle East respiratory syndrome coronavirus causes widespread infection and alveolar damage in human lungs. Am. J. Respir. Crit. Care Med. 2013, 188, 882– 886.
66. Bermingham, A.; Chand, M.A.; Brown, C.S.; Aarons, E.; Tong, C.; Langrish, C.; Hoschler, K.; Brown, K.; Galiano, M.; Myers, R.; et al. Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012. Eurosurveillance 2012, 17, 20290.
67. Corman, V.M.; Albarrak, A.M.; Omrani, A.S.; Albarrak, M.M.; Farah, M.E.; Almasri, M.; Muth, D.; Sieberg, A.; Meyer, B.; Assiri, A.M.; et al. Viral Shedding and Antibody Response in 37 Patients With Middle East Respiratory Syndrome Coronavirus Infection. Clin. Infect. Dis. 2016, 62, 477–483.
68. Drosten, C.; Seilmaier, M.; Corman, V.M.; Hartmann, W.; Scheible, G.; Sack, S.; Guggemos, W.; Kallies, R.; Muth, D.; Junglen, S.; et al. Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection. Lancet Infect. Dis. 2013, 13, 745–751.
69. Widagdo, W.; Raj, V.S.; Schipper, D.; Kolijn, K.; van Leenders, G.J.; Bosch, B.J.; Bensaid, A.; Segales, J.; Baumgartner, W.; Osterhaus, A.D.; et al. Differential Expression of the Middle East Respiratory Syndrome Coronavirus Receptor in the Upper Respiratory Tracts of Humans and Dromedary Camels. J. Virol. 2016, 90, 4838–4842.
70. Meyerholz, D.K.; Lambertz, A.M.; McCray, P.B. Jr. Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract: Implications for the Middle East Respiratory Syndrome. Am. J. Pathol. 2016, 186, 78–86.
71. Widagdo, W.; Begeman, L.; Schipper, D.; Run, P.R.V.; Cunningham, A.A.; Kley, N.; Reusken, C.B.; Haagmans, B.L.; van den Brand, J.M.A. Tissue Distribution of the MERS-Coronavirus Receptor in Bats. Sci. Rep. 2017, 7, 1193.
72. Munster, V.J.; Adney, D.R.; van Doremalen, N.; Brown, V.R.; Miazgowicz, K.L.; Milne-Price, S.; Bushmaker, T.; Rosenke, R.; Scott, D.; Hawkinson, A.; et al. Replication and shedding of MERS-CoV in Jamaican fruit bats (Artibeus jamaicensis). Sci. Rep. 2016, 6, 21878.
73. Annan, A.; Baldwin, H.J.; Corman, V.M.; Klose, S.M.; Owusu, M.; Nkrumah, E.E.; Badu, E.K.; Anti, P.; Agbenyega, O.; Meyer, B.; et al. Human betacoronavirus 2c EMC/2012-related viruses in bats, Ghana and Europe. Emerg. Infect. Dis. 2013, 19, 456–459.
74. Yang, L.; Wu, Z.; Ren, X.; Yang, F.; Zhang, J.; He, G.; Dong, J.; Sun, L.; Zhu, Y.; Zhang, S.; et al. MERS-related betacoronavirus in Vespertilio superans bats, China. Emerg. Infect. Dis. 2014, 20, 1260–1262.
75. Wacharapluesadee, S.; Sintunawa, C.; Kaewpom, T.; Khongnomnan, K.; Olival, K.J.; Epstein, J.H.; Rodpan, A.; Sangsri, P.; Intarut, N.; Chindamporn, A.; et al. Group C betacoronavirus in bat guano fertilizer, Thailand. Emerg. Infect. Dis. 2013, 19, 1349–1351.
76. Kim, H.K.; Yoon, S.W.; Kim, D.J.; Koo, B.S.; Noh, J.Y.; Kim, J.H.; Choi, Y.G.; Na, W.; Chang, K.T.; Song, D.; et al. Detection of Severe Acute Respiratory Syndrome-Like, Middle East Respiratory Syndrome-Like Bat Coronaviruses and Group H Rotavirus in Faeces of Korean Bats. Transbound. Emerg. Dis. 2016, 63, 365–372.
77. Corman, V.M.; Ithete, N.L.; Richards, L.R.; Schoeman, M.C.; Preiser, W.; Drosten, C.; Drexler, J.F. Rooting the phylogenetic tree of middle East respiratory syndrome coronavirus by characterization of a conspecific virus from an African bat. J. Virol. 2014, 88, 11297–11303.
78. Ithete, N.L.; Stoffberg, S.; Corman, V.M.; Cottontail, V.M.; Richards, L.R.; Schoeman, M.C.; Drosten, C.; Drexler, J.F.; Preiser, W. Close relative of human Middle East respiratory syndrome coronavirus in bat, South Africa. Emerg. Infect. Dis. 2013, 19, 1697–1699.
79. Anthony, S.J.; Gilardi, K.; Menachery, V.D.; Goldstein, T.; Ssebide, B.; Mbabazi, R.; Navarrete-Macias, I.; Liang, E.; Wells, H.; Hicks, A.; et al. Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus. MBio 2017, 8, e00373-17.
80. Luo, C.M.; Wang, N.; Yang, X.L.; Liu, H.Z.; Zhang, W.; Li, B.; Hu, B.; Peng, C.; Geng, Q.B.; Zhu, G.J.; et al. Discovery of Novel Bat Coronaviruses in South China That Use the Same Receptor as Middle East Respiratory Syndrome Coronavirus. J. Virol. 2018, 92, e00116-18.
81. Barlan, A.; Zhao, J.; Sarkar, M.K.; Li, K.; McCray, P.B. Jr.; Perlman, S.; Gallagher, T. Receptor variation and susceptibility to Middle East respiratory syndrome coronavirus infection. J. Virol. 2014, 88, 4953–4961.
82. van Doremalen, N.; Miazgowicz, K.L.; Milne-Price, S.; Bushmaker, T.; Robertson, S.; Scott, D.; Kinne, J.; McLellan, J.S.; Zhu, J.; Munster, V.J. Host species restriction of Middle East respiratory syndrome coronavirus through its receptor, dipeptidyl peptidase 4. J. Virol. 2014, 88, 9220–9232.
83. Widagdo, W.; Okba, N.M.A.; Richard, M.; de Muelder, D.; Bestebroer, T.M.; Lexmond, P.; J.M.A. v. d. B.; Haagmans, B.L.; Herfst, S. Middle East respiratory syndrome coronavirus transmission in rabbits. Unpublished work, 2019.
84. Vergara-Alert, J.; van den Brand, J.M.; Widagdo, W.; Munoz, M. t.; Raj, S.; Schipper, D.; Solanes, D.; Cordon, I.; Bensaid, A.; Haagmans, B.L.; et al. Livestock Susceptibility to Infection with Middle East Respiratory Syndrome Coronavirus. Emerg. Infect. Dis. 2017, 23, 232–240.
85. de Wit, E.; Feldmann, F.; Horne, E.; Martellaro, C.; Haddock, E.; Bushmaker, T.; Rosenke, K.; Okumura, A.; Rosenke, R.; Saturday, G.; et al. Domestic Pig Unlikely Reservoir for MERS-CoV. Emerg. Infect. Dis. 2017, 23, 985–988.
86. Adney, D.R.; Bielefeldt-Ohmann, H.; Hartwig, A.E.; Bowen, R.A. Infection, Replication, and Transmission of Middle East Respiratory Syndrome Coronavirus in Alpacas. Emerg. Infect. Dis. 2016, 22, 1031–1037.
87. Crameri, G.; Durr, P.A.; Klein, R.; Foord, A.; Yu, M.; Riddell, S.; Haining, J.; Johnson, D.; Hemida, M.G.; Barr, J.; et al. Experimental Infection and Response to Rechallenge of Alpacas with Middle East Respiratory Syndrome Coronavirus. Emerg. Infect. Dis. 2016, 22, 1071–1074.
88. Adney, D.R.; Brown, V.R.; Porter, S.M.; Bielefeldt-Ohmann, H.; Hartwig, A.E.; Bowen, R.A. Inoculation of Goats, Sheep, and Horses with MERS-CoV Does Not Result in Productive Viral Shedding. Viruses 2016, 8, 230.
89. Harris, S.R.; Robinson, C.; Steward, K.F.; Webb, K.S.; Paillot, R.; Parkhill, J.; Holden, M.T.; Waller, A.S. Genome specialization and decay of the strangles pathogen, Streptococcus equi, is driven by persistent infection. Genome Res. 2015, 25, 1360–1371.
90. Waller, A.S. Strangles: A pathogenic legacy of the war horse. Vet. Rec. 2016, 178, 91–92.
91. Reusken, C.B.; Haagmans, B.L.; Muller, M.A.; Gutierrez, C.; Godeke, G.J.; Meyer, B.; Muth, D.; Raj, V.S.; Smits-De Vries, L.; Corman, V.M.; et al. Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: A comparative serological study. Lancet Infect. Dis. 2013, 13, 859–866.
92. Hemida, M.G.; Perera, R.A.; Wang, P.; Alhammadi, M.A.; Siu, L.Y.; Li, M.; Poon, L.L.; Saif, L.; Alnaeem, A.; Peiris, M. Middle East Respiratory Syndrome (MERS) coronavirus seroprevalence in domestic livestock in Saudi Arabia, 2010 to 2013. Eurosurveillance 2013, 18, 20659.
93. van Doremalen, N.; Hijazeen, Z.S.; Holloway, P.; Al Omari, B.; McDowell, C.; Adney, D.; Talafha, H.A.; Guitian, J.; Steel, J.; Amarin, N.; et al. High Prevalence of Middle East Respiratory Coronavirus in Young Dromedary Camels in Jordan. Vector Borne Zoonotic Dis. 2017, 17, 155–159.
94. Meyer, B.; Garcia-Bocanegra, I.; Wernery, U.; Wernery, R.; Sieberg, A.; Muller, M.A.; Drexler, J.F.; Drosten, C.; Eckerle, I. Serologic assessment of possibility for MERS-CoV infection in equids. Emerg. Infect. Dis. 2015, 21, 181–182.
95. Hemida, M.G.; Chu, D.K.W.; Perera, R.; Ko, R.L.W.; So, R.T.Y.; Ng, B.C.Y.; Chan, S.M.S.; Chu, S.; Alnaeem, A.A.; Alhammadi, M.A.; et al. Coronavirus infections in horses in Saudi Arabia and Oman. Transbound. Emerg. Dis. 2017, 64, 2093–2103.
96. Ali, M.; El-Shesheny, R.; Kandeil, A.; Shehata, M.; Elsokary, B.; Gomaa, M.; Hassan, N.; El Sayed, A.; El-Taweel, A.; Sobhy, H.; et al. Cross-sectional surveillance of Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels and other mammals in Egypt, August 2015 to January 2016. Eurosurveillance 2017, 22, 30487.
97. David, D.; Rotenberg, D.; Khinich, E.; Erster, O.; Bardenstein, S.; van Straten, M.; Okba, N.M.A.; Raj, S.V.; Haagmans, B.L.; Miculitzki, M.; et al. Middle East respiratory syndrome coronavirus specific antibodies in naturally exposed Israeli llamas, alpacas and camels. One Health 2018, 5, 65–68.
98. Reusken, C.B.; Schilp, C.; Raj, V.S.; De Bruin, E.; Kohl, R.H.; Farag, E.A.; Haagmans, B.L.; Al-Romaihi, H.; Le Grange, F.; Bosch, B.J.; et al. MERS-CoV Infection of Alpaca in a Region Where MERS-CoV is Endemic. Emerg. Infect. Dis. 2016, 22, 1129.
99. Vergara-Alert, J.; Raj, V.S.; Munoz, M.; Abad, F.X.; Cordon, I.; Haagmans, B.L.; Bensaid, A.; Segales, J. Middle East respiratory syndrome coronavirus experimental transmission using a pig model. Transbound. Emerg. Dis. 2017, 64, 1342–1345.
100. A protein. Unpublished work, 2019.
101. Yang, Y.; Du, L.; Liu, C.; Wang, L.; Ma, C.; Tang, J.; Baric, R.S.; Jiang, S.; Li, F. Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proc. Natl. Acad. Sci. USA 2014, 111, 12516–12521.
102. Nam, H.S.; Park, J.W.; Ki, M.; Yeon, M.Y.; Kim, J.; Kim, S.W. High fatality rates and associated factors in two hospital outbreaks of MERS in Daejeon, the Republic of Korea. Int. J. Infect. Dis. 2017, 58, 37–42.
103. Alraddadi, B.M.; Watson, J.T.; Almarashi, A.; Abedi, G.R.; Turkistani, A.; Sadran, M.; Housa, A.; Almazroa, M.A.; Alraihan, N.; Banjar, A.; et al. Risk Factors for Primary Middle East Respiratory Syndrome Coronavirus Illness in Humans, Saudi Arabia, 2014. Emerg. Infect. Dis. 2016, 22, 49–55.
104. Seys, L.J.M.; Widagdo, W.; Verhamme, F.M.; Kleinjan, A.; Janssens, W.; Joos, G.F.; Bracke, K.R.; Haagmans, B.L.; Brusselle, G.G. DPP4, the Middle East Respiratory Syndrome Coronavirus Receptor, is Upregulated in Lungs of Smokers and Chronic Obstructive Pulmonary Disease Patients. Clin. Infect. Dis. 2018, 66, 45–53.
105. Dahlin, K.; Mager, E.M.; Allen, L.; Tigue, Z.; Goodglick, L.; Wadehra, M.; Dobbs, L. Identification of genes differentially expressed in rat alveolar type I cells. Am. J. Respir. Cell. Mol. Biol. 2004, 31, 309–316.
106. Evans, M.J.; Cabral, L.J.; Stephens, R.J.; Freeman, G. Renewal of alveolar epithelium in the rat following exposure to NO2. Am. J. Pathol. 1973, 70, 175–198.
107. Alsaad, K.O.; Hajeer, A.H.; Al Balwi, M.; Al Moaiqel, M.; Al Oudah, N.; Al Ajlan, A.; AlJohani, S.; Alsolamy, S.; Gmati, G.E.; Balkhy, H.; et al. Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection-clinicopathological and ultrastructural study. Histopathology. 2018, 72, 516–524.
108. Haagmans, B.L.; Kuiken, T.; Martina, B.E.; Fouchier, R.A.; Rimmelzwaan, G.F.; van Amerongen, G.; van Riel, D.; de Jong, T.; Itamura, S.; Chan, K.H.; et al. Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat. Med. 2004, 10, 290–293.
109. Chen, Z.; Bao, L.; Chen, C.; Zou, T.; Xue, Y.; Li, F.; Lv, Q.; Gu, S.; Gao, X.; Cui, S.; et al. Human Neutralizing Monoclonal Antibody Inhibition of Middle East Respiratory Syndrome Coronavirus Replication in the Common Marmoset. J. Infect. Dis. 2017, 215, 1807–1815.
110. Chan, J.F.; Yao, Y.; Yeung, M.L.; Deng, W.; Bao, L.; Jia, L.; Li, F.; Xiao, C.; Gao, H.; Yu, P.; et al. Treatment With Lopinavir/Ritonavir or Interferon-beta1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J. Infect. Dis. 2015, 212, 1904–1913.
111. Falzarano, D.; de Wit, E.; Feldmann, F.; Rasmussen, A.L.; Okumura, A.; Peng, X.; Thomas, M.J.; van Doremalen, N.; Haddock, E.; Nagy, L.; et al. Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS. Pathog. 2014, 10, e1004250.
112. Widagdo, W.; Wiersma, L.C.M.; Smits, S.L.; de Vries, R.D.; Schipper, D.; Raj, V.S.; van den Ham, H.J.; Brown, R.; Zambon, M.; Kondova, I.; et al. DPP4-expressing type I pneumocytes in a fatal human MERS-coronavirus case. Unpublished work, 2019.
113. Li, K.; Wohlford-Lenane, C.; Perlman, S.; Zhao, J.; Jewell, A.K.; Reznikov, L.R.; Gibson-Corley, K.N.; Meyerholz, D.K.; McCray, P.B. Jr. Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4. J. Infect. Dis. 2016, 213, 712–722.
114. Algaissi, A.; Agrawal, A.S.; Han, S.; Peng, B.H.; Luo, C.; Li, F.; Chan, T.S.; Couch, R.B.; Tseng, C.K. Elevated Human Dipeptidyl Peptidase 4 Expression Reduces the Susceptibility of hDPP4 Transgenic Mice to Middle East Respiratory Syndrome Coronavirus Infection and Disease. J. Infect. Dis. 2018, 219, 829–835.
115. Prescott, J.; Falzarano, D.; de Wit, E.; Hardcastle, K.; Feldmann, F.; Haddock, E.; Scott, D.; Feldmann, H.; Munster, V.J. Pathogenicity and Viral Shedding of MERS-CoV in Immunocompromised Rhesus Macaques. Front. Immunol. 2018, 9, 205.
116. Kim, S.H.; Ko, J.H.; Park, G.E.; Cho, S.Y.; Ha, Y.E.; Kang, J.M.; Kim, Y.J.; Huh, H.J.; Ki, C.S.; Jeong, B.H.; et al. Atypical presentations of MERS-CoV infection in immunocompromised hosts. J. Infect. Chemother. 2017, 23, 769–773.
117. Zhao, J.; Alshukairi, A.N.; Baharoon, S.A.; Ahmed, W.A.; Bokhari, A.A.; Nehdi, A.M.; Layqah, L.A.; Alghamdi, M.G.; Al Gethamy, M.M.; Dada, A.M.; et al. Recovery from the Middle East respiratory syndrome is associated with antibody and T-cell responses. Sci. Immunol. 2017, 2, eaan5393.
118. Coleman, C.M.; Sisk, J.M.; Halasz, G.; Zhong, J.; Beck, S.E.; Matthews, K.L.; Venkataraman, T.; Rajagopalan, S.; Kyratsous, C.A.; Frieman, M.B. CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome. J. Virol. 2017, 91, e01825-16.
119. Hart, B.J.; Dyall, J.; Postnikova, E.; Zhou, H.; Kindrachuk, J.; Johnson, R.F.; Olinger, G.G. Jr.; Frieman, M.B.; Holbrook, M.R.; Jahrling, P.B.; et al. Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J. Gen. Virol. 2014, 95 Pt 3, 571–577.
120. Oudshoorn, D.; van der Hoeven, B.; Limpens, R.W.; Beugeling, C.; Snijder, E.J.; Barcena, M.; Kikkert, M. Antiviral Innate Immune Response Interferes with the Formation of Replication-Associated Membrane Structures Induced by a Positive-Strand RNA Virus. MBio 2016, 7, e01991-16.
121. Uno, K.; Yagi, K.; Yoshimori, M.; Tanigawa, M.; Yoshikawa, T.; Fujita, S. IFN production ability and healthy ageing: Mixed model analysis of a 24 year longitudinal study in Japan. BMJ Open 2013, 3, e002113.
122. Li, G.; Ju, J.; Weyand, C.M.; Goronzy, J.J. Age-Associated Failure To Adjust Type I IFN Receptor Signaling Thresholds after T Cell Activation. J. Immunol. 2015, 195, 865–874.
123. Channappanavar, R.; Fehr, A.R.; Vijay, R.; Mack, M.; Zhao, J.; Meyerholz, D.K.; Perlman, S. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe 2016, 19, 181–193.
124. Zumla, A.; Hui, D.S.; Perlman, S. Middle East respiratory syndrome. Lancet 2015, 386, 995–1007.
125. Alfaraj, S.H.; Al-Tawfiq, J.A.; Alzahrani, N.A.; Altwaijri, T.A.; Memish, Z.A. The impact of co-infection of influenza A virus on the severity of Middle East Respiratory Syndrome Coronavirus. J. Infect. 2017, 74, 521–523.
126. Chu, D.K.W.; Hui, K.P.Y.; Perera, R.; Miguel, E.; Niemeyer, D.; Zhao, J.; Channappanavar, R.; Dudas, G.; Oladipo, J.O.; Traore, A.; et al. MERS coronaviruses from camels in Africa exhibit region-dependent genetic diversity. Proc. Natl. Acad. Sci. USA 2018, 115, 3144–3149.
127. Vergara-Alert, J.; van den Brand, J.M.; Widagdo, W.; Munoz, M. t.; Raj, S.; Schipper, D.; Solanes, D.; Cordon, I.; Bensaid, A.; Haagmans, B.L.; et al. Livestock Susceptibility to Infection with Middle East Respiratory Syndrome Coronavirus. Emerg. Infect. Dis. 2017, 23, 232–240.
128. Payne, D.C.; Biggs, H.M.; Al-Abdallat, M.M.; Alqasrawi, S.; Lu, X.; Abedi, G.R.; Haddadin, A.; Iblan, I.; Alsanouri, T.; Al Nsour, M.; et al. Multihospital Outbreak of a Middle East Respiratory Syndrome Coronavirus Deletion Variant, Jordan: A Molecular, Serologic, and Epidemiologic Investigation. Open Forum Infect. Dis. 2018, 5, ofy095.
129. Lamers, M.M.; Raj, V.S.; Shafei, M.; Ali, S.S.; Abdallh, S.M.; Gazo, M.; Nofal, S.; Lu, X.; Erdman, D.D.; Koopmans, M.P.; et al. Deletion Variants of Middle East Respiratory Syndrome Coronavirus from Humans, Jordan, 2015. Emerg. Infect. Dis. 2016, 22, 716–719.