Modeling pathogenesis of emergent and pre-emergent human coronaviruses in mice

Mammalian Genome

Volumn 29, Issue 7-8, 2018, Pages 367-383

  Cockrell, Adam S ^a   Leist, Sarah R ^a   Douglas, Madeline G ^a   Baric, Ralph S ^a,b  

^a University of North Carolina at Chapel Hill   (United States)

^b UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CORONAVIRIDAE; CORONAVIRUS INFECTION; HUMAN; MAMMAL; MORBIDITY; MORTALITY RATE; MOUSE MODEL; NONHUMAN; PANDEMIC; PHENOTYPE; PREDICTIVE VALUE; REVERSE GENETICS; REVIEW; VIRUS CELL INTERACTION; VIRUS PATHOGENESIS; VIRUS TRANSMISSION; ANIMAL; COMMUNICABLE DISEASE; CORONAVIRINAE; DISEASE MODEL; DISEASE PREDISPOSITION; GENETICS; HOST PATHOGEN INTERACTION; IMMUNOLOGY; MOUSE; PHYSIOLOGY; VIROLOGY;

ANIMALS; COMMUNICABLE DISEASES, EMERGING; CORONAVIRUS; CORONAVIRUS INFECTIONS; DISEASE MODELS, ANIMAL; DISEASE SUSCEPTIBILITY; HOST-PATHOGEN INTERACTIONS; HUMANS; MICE;

EID: 85050646753     PISSN: 09388990     EISSN: 14321777     Source Type: Journal    
DOI: 10.1007/s00335-018-9760-9     Document Type: Review

References (116)

1. Agnihothram S, Yount BL, Donaldson EF, Huynh J, Menachery VD, Gralinski LE, Graham RL, Becker MM, Tomar S, Scobey TD, Osswald HL, Whitmore A, Gopal R, Ghosh AK, Mesecar A, Zambon M, Heise M, Denison MR, Baric RS (2014) A mouse model for betacoronavirus subgroup 2c using a bat coronavirus strain HKU5 variant. mBio. 10.1128/mBio.00047-14
2. Agrawal AS, Garron T, Tao X, Peng BH, Wakamiya M, Chan TS, Couch RB, Tseng CT (2015) Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol 89:3659–3670
3. Alsaad KO, Hajeer AH, Al Balwi M, Al Moaiqel M, Al Oudah N, Al Ajlan A, AlJohani S, Alsolamy S, Gmati GE, Balkhy H, Al-Jahdali HH, Baharoon SA, Arabi YM (2017) Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection—clinicopathological and ultrastructural study. Histopathology. 10.1111/his.13379
4. 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 (2017) Middle East respiratory syndrome. N Engl J Med 376:584–594
5. Becker MM, Graham RL, Donaldson EF, Rockx B, Sims AC, Sheahan T, Pickles RJ, Corti D, Johnston RE, Baric RS, Denison MR (2008) Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice. Proc Natl Acad Sci USA 105:19944–19949
6. Bolles M, Deming D, Long K, Agnihothram S, Whitmore A, Ferris M, Funkhouser W, Gralinski L, Totura A, Heise M, Baric RS (2011) A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J Virol 85:12201–12215
7. Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, Walmsley SL, Mazzulli T, Avendano M, Derkach P, Ephtimios IE, Kitai I, Mederski BD, Shadowitz SB, Gold WL, Hawryluck LA, Rea E, Chenkin JS, Cescon DW, Poutanen SM, Detsky AS (2003) Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 289:2801–2809
8. Bottomly D, Ferris MT, Aicher LD, Rosenzweig E, Whitmore A, Aylor DL, Haagmans BL, Gralinski LE, Bradel-Tretheway BG, Bryan JT, Threadgill DW, de Villena FP, Baric RS, Katze MG, Heise M, McWeeney SK (2012) Expression quantitative trait Loci for extreme host response to influenza a in pre-collaborative cross mice. G3 (Bethesda) 2:213–221
9. Brinkmeyer-Langford CL, Rech R, Amstalden K, Kochan KJ, Hillhouse AE, Young C, Welsh CJ, Threadgill DW (2017) Host genetic background influences diverse neurological responses to viral infection in mice. Sci Rep 7:12194
10. Chan VS, Chan KY, Chen Y, Poon LL, Cheung AN, Zheng B, Chan KH, Mak W, Ngan HY, Xu X, Screaton G, Tam PK, Austyn JM, Chan LC, Yip SP, Peiris M, Khoo US, Lin CL (2006) Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection. Nat Genet 38:38–46
11. Chan KY, Ching JC, Xu MS, Cheung AN, Yip SP, Yam LY, Lai ST, Chu CM, Wong AT, Song YQ, Huang FP, Liu W, Chung PH, Leung GM, Chow EY, Chan EY, Chan JC, Ngan HY, Tam P, Chan LC, Sham P, Chan VS, Peiris M, Lin SC, Khoo US (2007) Association of ICAM3 genetic variant with severe acute respiratory syndrome. J Infect Dis 196:271–280
12. Ching JC, Chan KY, Lee EH, Xu MS, Ting CK, So TM, Sham PC, Leung GM, Peiris JS, Khoo US (2010) Significance of the myxovirus resistance A (MxA) gene – 123C> a single-nucleotide polymorphism in suppressed interferon beta induction of severe acute respiratory syndrome coronavirus infection. J Infect Dis 201:1899–1908
13. Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, Beatty J, Beavis WD, Belknap JK, Bennett B, Berrettini W, Bleich A, Bogue M, Broman KW, Buck KJ, Buckler E, Burmeister M, Chesler EJ, Cheverud JM, Clapcote S, Cook MN, Cox RD, Crabbe JC, Crusio WE, Darvasi A, Deschepper CF, Doerge RW, Farber CR, Forejt J, Gaile D, Garlow SJ, Geiger H, Gershenfeld H, Gordon T, Gu J, Gu W, de Haan G, Hayes NL, Heller C, Himmelbauer H, Hitzemann R, Hunter K, Hsu HC, Iraqi FA, Ivandic B, Jacob HJ, Jansen RC, Jepsen KJ, Johnson DK, Johnson TE, Kempermann G, Kendziorski C, Kotb M, Kooy RF, Llamas B, Lammert F, Lassalle JM, Lowenstein PR, Lu L, Lusis A, Manly KF, Marcucio R, Matthews D, Medrano JF, Miller DR, Mittleman G, Mock BA, Mogil JS, Montagutelli X, Morahan G, Morris DG, Mott R, Nadeau JH, Nagase H, Nowakowski RS, O’Hara BF, Osadchuk AV, Page GP, Paigen B, Paigen K, Palmer AA, Pan HJ, Peltonen-Palotie L, Peirce J, Pomp D, Pravenec M, Prows DR, Qi Z, Reeves RH, Roder J, Rosen GD, Schadt EE, Schalkwyk LC, Seltzer Z, Shimomura K, Shou S, Sillanpaa MJ, Siracusa LD, Snoeck HW, Spearow JL, Svenson K, Tarantino LM, Threadgill D, Toth LA, Valdar W, de Villena FP, Warden C, Whatley S, Williams RW, Wiltshire T, Yi N, Zhang D, Zhang M, Zou F, Complex Trait Consortium (2004) The collaborative cross, a community resource for the genetic analysis of complex traits. Nat Genet 36:1133–1137
14. Cockrell AS, Peck KM, Yount BL, Agnihothram SS, Scobey T, Curnes NR, Baric RS, Heise MT (2014) Mouse dipeptidyl peptidase 4 is not a functional receptor for Middle East respiratory syndrome coronavirus infection. J Virol 88:5195–5199
15. Cockrell AS, Yount BL, Scobey T, Jensen K, Douglas M, Beall A, Tang XC, Marasco WA, Heise MT, Baric RS (2016) A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nat Microbiol 2:16226
16. Cockrell AS, Beall A, Yount B, Baric R (2017) Efficient reverse genetic systems for rapid genetic manipulation of emergent and preemergent infectious coronaviruses. Methods Mol Biol (Clifton NJ) 1602:59–81
17. Coleman CM, Matthews KL, Goicochea L, Frieman MB (2014) Wild-type and innate immune-deficient mice are not susceptible to the Middle East respiratory syndrome coronavirus. J Gen Virol 95:408–412
18. Coleman CM, Sisk JM, Halasz G, Zhong J, Beck SE, Matthews KL, Venkataraman T, Rajagopalan S, Kyratsous CA, Frieman MB (2017) CD8 + T cells and macrophages regulate pathogenesis in a mouse model of Middle East respiratory syndrome. J Virol. 10.1128/JVI.01825-16
19. Day CW, Baric R, Cai SX, Frieman M, Kumaki Y, Morrey JD, Smee DF, Barnard DL (2009) A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo. Virology 395:210–222
20. de Wit E, Prescott J, Baseler L, Bushmaker T, Thomas T, Lackemeyer MG, Martellaro C, Milne-Price S, Haddock E, Haagmans BL, Feldmann H, Munster VJ (2013a) The Middle East respiratory syndrome coronavirus (MERS-CoV) does not replicate in Syrian hamsters. PLoS ONE 8:e69127
21. de Wit E, Rasmussen AL, Falzarano D, Bushmaker T, Feldmann F, Brining DL, Fischer ER, Martellaro C, Okumura A, Chang J, Scott D, Benecke AG, Katze MG, Feldmann H, Munster VJ (2013b) Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc Natl Acad Sci USA 110:16598–16603
22. de Wit E, van Doremalen N, Falzarano D, Munster VJ (2016) SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 14:523–534
23. Deng X, Agnihothram S, Mielech AM, Nichols DB, Wilson MW, StJohn SE, Larsen SD, Mesecar AD, Lenschow DJ, Baric RS, Baker SC (2014) A chimeric virus-mouse model system for evaluating the function and inhibition of papain-like proteases of emerging coronaviruses. J Virol 88:11825–11833
24. Doench JG (2018) Am I ready for CRISPR? A user’s guide to genetic screens. Nat Rev Genet 19:67–80
25. Donnelly CA, Ghani AC, Leung GM, Hedley AJ, Fraser C, Riley S, Abu-Raddad LJ, Ho L-M, Thach T-Q, Chau P, Chan K-P, Lam T-H, Tse L-Y, Tsang T, Liu S-H, Kong JHB, Lau EMC, Ferguson NM, Anderson RM (2003) Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong. Lancet 361:1761–1766
26. Dornemann J, Burzio C, Ronsse A, Sprecher A, De Clerck H, Van Herp M, Kolie MC, Yosifiva V, Caluwaerts S, McElroy AK, Antierens A (2017) First newborn baby to receive experimental therapies survives Ebola virus disease. J Infect Dis 215:171–174
27. Douglas MG, Kocher JF, Scobey T, Baric RS, Cockrell AS (2018) Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease. Virology 517:98–107
28. Dyall J, Gross R, Kindrachuk J, Johnson RF, Olinger GG Jr, Hensley LE, Frieman MB, Jahrling PB (2017) Middle East respiratory syndrome and severe acute respiratory syndrome: current therapeutic options and potential targets for novel therapies. Drugs 77:1935–1966
29. Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB, Gen II, Investigators M, Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P (2012) IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484:519–523
30. Falzarano D, de Wit E, Feldmann F, Rasmussen AL, Okumura A, Peng X, Thomas MJ, van Doremalen N, Haddock E, Nagy L, LaCasse R, Liu T, Zhu J, McLellan JS, Scott DP, Katze MG, Feldmann H, Munster VJ (2014) Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog 10:e1004250
31. Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel DB, Navre M, Shi L, Skene RJ, Asakawa T, Takeuchi K, Xu R, Webb DR, Gwaltney SL 2nd (2007) Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J Med Chem 50:2297–2300
32. Ferris MT, Aylor DL, Bottomly D, Whitmore AC, Aicher LD, Bell TA, Bradel-Tretheway B, Bryan JT, Buus RJ, Gralinski LE, Haagmans BL, McMillan L, Miller DR, Rosenzweig E, Valdar W, Wang J, Churchill GA, Threadgill DW, McWeeney SK, Katze MG, Pardo-Manuel de Villena F, Baric RS, Heise MT (2013) Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. PLoS Pathog 9:e1003196
33. Forni D, Cagliani R, Clerici M, Sironi M (2017) Molecular evolution of human coronavirus genomes. Trends Microbiol 25:35–48
34. Forton JT, Rowlands K, Rockett K, Hanchard N, Herbert M, Kwiatkowski DP, Hull J (2009) Genetic association study for RSV bronchiolitis in infancy at the 5q31 cytokine cluster. Thorax 64:345–352
35. Frieman MB, Chen J, Morrison TE, Whitmore A, Funkhouser W, Ward JM, Lamirande EW, Roberts A, Heise M, Subbarao K, Baric RS (2010) SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog 6:e1000849
36. Frieman M, Yount B, Agnihothram S, Page C, Donaldson E, Roberts A, Vogel L, Woodruff B, Scorpio D, Subbarao K, Baric RS (2012) Molecular determinants of severe acute respiratory syndrome coronavirus pathogenesis and virulence in young and aged mouse models of human disease. J Virol 86:884–897
37. Ge X, Li Y, Yang X, Zhang H, Zhou P, Zhang Y, Shi Z (2012) Metagenomic analysis of viruses from bat fecal samples reveals many novel viruses in insectivorous bats in China. J Virol 86:4620–4630
38. Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH, Mazet JK, Hu B, Zhang W, Peng C, Zhang YJ, Luo CM, Tan B, Wang N, Zhu Y, Crameri G, Zhang SY, Wang LF, Daszak P, Shi ZL (2013) Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 503:535–538
39. Glass WG, Subbarao K, Murphy B, Murphy PM (2004) Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol 173:4030–4039
40. Graham RL, Baric RS (2010) Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission. J Virol 84:3134–3146
41. Gralinski LE, Ferris MT, Aylor DL, Whitmore AC, Green R, Frieman MB, Deming D, Menachery VD, Miller DR, Buus RJ, Bell TA, Churchill GA, Threadgill DW, Katze MG, McMillan L, Valdar W, Heise MT, Pardo-Manuel de Villena F, Baric RS (2015) Genome wide identification of SARS-CoV susceptibility loci using the collaborative cross. PLoS Genet 11:e1005504
42. Gralinski LE, Menachery VD, Morgan AP, Totura AL, Beall A, Kocher J, Plante J, Harrison-Shostak DC, Schafer A, Pardo-Manuel de Villena F, Ferris MT, Baric RS (2017) Allelic variation in the toll-like receptor adaptor protein Ticam2 contributes to SARS-coronavirus pathogenesis in mice. G3 (Bethesda) 7:1653–1663
43. Green R, Wilkins C, Thomas S, Sekine A, Hendrick DM, Voss K, Ireton RC, Mooney M, Go JT, Choonoo G, Jeng S, de Villena FP, Ferris MT, McWeeney S, Gale M Jr (2017) Oas1b-dependent immune transcriptional profiles of West Nile virus infection in the collaborative cross. G3 (Bethesda) 7:1665–1682
44. Haagmans BL, van den Brand JM, Raj VS, Volz A, Wohlsein P, Smits SL, Schipper D, Bestebroer TM, Okba N, Fux R, Bensaid A, Solanes Foz D, Kuiken T, Baumgartner W, Segales J, Sutter G, Osterhaus AD (2016) An orthopoxvirus-based vaccine reduces virus excretion after MERS-CoV infection in dromedary camels. Science 351:77–81
45. He B, Zhang Y, Xu L, Yang W, Yang F, Feng Y, Xia L, Zhou J, Zhen W, Feng Y, Guo H, Zhang H, Tu C (2014) Identification of diverse alphacoronaviruses and genomic characterization of a novel severe acute respiratory syndrome-like coronavirus from bats in China. J Virol 88:7070–7082
46. Hogan RJ, Gao G, Rowe T, Bell P, Flieder D, Paragas J, Kobinger GP, Wivel NA, Crystal RG, Boyer J, Feldmann H, Voss TG, Wilson JM (2004) Resolution of primary severe acute respiratory syndrome-associated coronavirus infection requires Stat1. J Virol 78:11416–11421
47. Johnson RF, Via LE, Kumar MR, Cornish JP, Yellayi S, Huzella L, Postnikova E, Oberlander N, Bartos C, Ork BL, Mazur S, Allan C, Holbrook MR, Solomon J, Johnson JC, Pickel J, Hensley LE, Jahrling PB (2015) Intratracheal exposure of common marmosets to MERS-CoV Jordan-n3/2012 or MERS-CoV EMC/2012 isolates does not result in lethal disease. Virology 485:422–430
48. Johnson RF, Bagci U, Keith L, Tang X, Mollura DJ, Zeitlin L, Qin J, Huzella L, Bartos CJ, Bohorova N, Bohorov O, Goodman C, Kim do H, Paulty MH, Velasco J, Whaley KJ, Johnson JC, Pettitt J, Ork BL, Solomon J, Oberlander N, Zhu Q, Sun J, Holbrook MR, Olinger GG, Baric RS, Hensley LE, Jahrling PB, Marasco WA (2016) 3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012. Virology 490:49–58
49. Kalter SS (1949) Hemagglutinating behavior of mouse and egg-adapted type A (PR8) influenza virus. Science (New York) 110:184
50. Kenney AD, Dowdle JA, Bozzacco L, McMichael TM, St Gelais C, Panfil AR, Sun Y, Schlesinger LS, Anderson MZ, Green PL, Lopez CB, Rosenberg BR, Wu L, Yount JS (2017) Human genetic determinants of viral diseases. Annu Rev Genet 51:241–263
51. Kim H, Kim JS (2014) A guide to genome engineering with programmable nucleases. Nat Rev Genet 15:321–334
52. Klemann C, Wagner L, Stephan M, von Horsten S (2016) Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system. Clin Exp Immunol 185:1–21
53. Lau SK, Woo PC, Li KS, Huang Y, Tsoi HW, Wong BH, Wong SS, Leung SY, Chan KH, Yuen KY (2005) Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc Natl Acad Sci USA 102:14040–14045
54. Lau SK, Li KS, Huang Y, Shek CT, Tse H, Wang M, Choi GK, Xu H, Lam CS, Guo R, Chan KH, Zheng BJ, Woo PC, Yuen KY (2010) Ecoepidemiology and complete genome comparison of different strains of severe acute respiratory syndrome-related Rhinolophus bat coronavirus in China reveal bats as a reservoir for acute, self-limiting infection that allows recombination events. J Virol 84:2808–2819
55. Lau SK, Feng Y, Chen H, Luk HK, Yang WH, Li KS, Zhang YZ, Huang Y, Song ZZ, Chow WN, Fan RY, Ahmed SS, Yeung HC, Lam CS, Cai JP, Wong SS, Chan JF, Yuen KY, Zhang HL, Woo PC (2015) Severe acute respiratory syndrome (SARS) coronavirus ORF8 protein is acquired from SARS-related coronavirus from greater horseshoe bats through recombination. J Virol 89:10532–10547
56. Lee SI (2015) Costly lessons from the 2015 Middle East respiratory syndrome coronavirus outbreak in Korea. J Prev Med Public Health 48:274–276
57. Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, Gibson-Corley KN, Meyerholz DK, McCray PB Jr (2016) Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis 213:712–722
58. Li K, Wohlford-Lenane CL, Channappanavar R, Park JE, Earnest JT, Bair TB, Bates AM, Brogden KA, Flaherty HA, Gallagher T, Meyerholz DK, Perlman S, McCray PB Jr (2017) Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. Proc Natl Acad Sci USA 114:E3119–E3128
59. Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF (2013) Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature 500:227–231
60. McCray PB Jr, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L, Netland J, Jia HP, Halabi C, Sigmund CD, Meyerholz DK, Kirby P, Look DC, Perlman S (2007) Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol 81:813–821
61. Menachery VD, Yount BL Jr, Debbink K, Agnihothram S, Gralinski LE, Plante JA, Graham RL, Scobey T, Ge XY, Donaldson EF, Randell SH, Lanzavecchia A, Marasco WA, Shi ZL, Baric RS (2015) A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat Med 21:1508–1513
62. Menachery VD, Yount BL Jr, Sims AC, Debbink K, Agnihothram SS, Gralinski LE, Graham RL, Scobey T, Plante JA, Royal SR, Swanstrom J, Sheahan TP, Pickles RJ, Corti D, Randell SH, Lanzavecchia A, Marasco WA, Baric RS (2016) SARS-like WIV1-CoV poised for human emergence. Proc Natl Acad Sci USA 113:3048–3053
63. Menachery VD, Graham RL, Baric RS (2017a) Jumping species-a mechanism for coronavirus persistence and survival. Curr Opin Virol 23:1–7
64. Menachery VD, Gralinski LE, Mitchell HD, Dinnon KH 3rd, Leist SR, Yount BL Jr, Graham RL, McAnarney ET, Stratton KG, Cockrell AS, Debbink K, Sims AC, Waters KM, Baric RS (2017b) Middle East Respiratory Syndrome coronavirus nonstructural protein 16 is necessary for interferon resistance and viral pathogenesis. mSphere. 10.1128/mSphere.00346-17
65. Menachery VD, Mitchell HD, Cockrell AS, Gralinski LE, Yount BL Jr, Graham RL, McAnarney ET, Douglas MG, Scobey T, Beall A, Dinnon K 3rd, Kocher JF, Hale AE, Stratton KG, Waters KM, Baric RS (2017c) MERS-CoV accessory ORFs play key role for infection and pathogenesis. mBio. 10.1128/mBio.00665-17
66. Mills TC, Rautanen A, Elliott KS, Parks T, Naranbhai V, Ieven MM, Butler CC, Little P, Verheij T, Garrard CS, Hinds C, Goossens H, Chapman S, Hill AV (2014) IFITM3 and susceptibility to respiratory viral infections in the community. J Infect Dis 209:1028–1031
67. Munster VJ, de Wit E, Feldmann H (2013) Pneumonia from human coronavirus in a macaque model. N Engl J Med 368:1560–1562
68. Munster VJ, Wells D, Lambe T, Wright D, Fischer RJ, Bushmaker T, Saturday G, van Doremalen N, Gilbert SC, de Wit E, Warimwe GM (2017) Protective efficacy of a novel simian adenovirus vaccine against lethal MERS-CoV challenge in a transgenic human DPP4 mouse model. NPJ Vaccines 2:28
69. Muthumani K, Falzarano D, Reuschel EL, Tingey C, Flingai S, Villarreal DO, Wise M, Patel A, Izmirly A, Aljuaid A, Seliga AM, Soule G, Morrow M, Kraynyak KA, Khan AS, Scott DP, Feldmann F, LaCasse R, Meade-White K, Okumura A, Ugen KE, Sardesai NY, Kim JJ, Kobinger G, Feldmann H, Weiner DB (2015) A synthetic consensus anti-spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates. Sci Transl Med 7:301ra132
70. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 82:7264–7275
71. Ng DL, Al Hosani F, Keating MK, Gerber SI, Jones TL, Metcalfe MG, Tong S, Tao Y, Alami NN, Haynes LM, Mutei MA, Abdel-Wareth L, Uyeki TM, Swerdlow DL, Barakat M, Zaki SR (2016) Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014. Am J Pathol 186:652–658
72. Niu D, Wei HJ, Lin L, George H, Wang T, Lee IH, Zhao HY, Wang Y, Kan Y, Shrock E, Lesha E, Wang G, Luo Y, Qing Y, Jiao D, Zhao H, Zhou X, Wang S, Wei H, Guell M, Church GM, Yang L (2017) Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science (New York) 357, 1303–1307
73. Ohnuma K, Dang NH, Morimoto C (2008) Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function. Trends Immunol 29:295–301
74. Okba NM, Raj VS, Haagmans BL (2017) Middle East respiratory syndrome coronavirus vaccines: current status and novel approaches. Curr Opin Virol 23:49–58
75. Pasanen A, Karjalainen MK, Bont L, Piippo-Savolainen E, Ruotsalainen M, Goksor E, Kumawat K, Hodemaekers H, Nuolivirta K, Jartti T, Wennergren G, Hallman M, Ramet M, Korppi M (2017) Genome-wide association study of polymorphisms predisposing to bronchiolitis. Sci Rep 7:41653
76. Pascal KE, Coleman CM, Mujica AO, Kamat V, Badithe A, Fairhurst J, Hunt C, Strein J, Berrebi A, Sisk JM, Matthews KL, Babb R, Chen G, Lai KM, Huang TT, Olson W, Yancopoulos GD, Stahl N, Frieman MB, Kyratsous CA (2015) Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. Proc Natl Acad Sci USA 112:8738–8743
77. Patarcic I, Gelemanovic A, Kirin M, Kolcic I, Theodoratou E, Baillie KJ, de Jong MD, Rudan I, Campbell H, Polasek O (2015) The role of host genetic factors in respiratory tract infectious diseases: systematic review, meta-analyses and field synopsis. Sci Rep 5:16119
78. Peck KM, Cockrell AS, Yount BL, Scobey T, Baric RS, Heise MT (2015) Glycosylation of mouse DPP4 plays a role in inhibiting Middle East respiratory syndrome coronavirus infection. J Virol 89:4696–4699
79. Peck KM, Scobey T, Swanstrom J, Jensen KL, Burch CL, Baric RS, Heise MT (2017) Permissivity of Dipeptidyl peptidase 4 orthologs to Middle East respiratory syndrome coronavirus is governed by glycosylation and other complex determinants. J Virol. 10.1128/JVI.00534-17
80. Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL (2013) Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495:251–254
81. Raj VS, Smits SL, Provacia LB, van den Brand JM, Wiersma L, Ouwendijk WJ, Bestebroer TM, Spronken MI, van Amerongen G, Rottier PJ, Fouchier RA, Bosch BJ, Osterhaus AD, Haagmans BL (2014) Adenosine deaminase acts as a natural antagonist for dipeptidyl peptidase 4-mediated entry of the Middle East respiratory syndrome coronavirus. J Virol 88:1834–1838
82. Rasmussen AL, Okumura A, Ferris MT, Green R, Feldmann F, Kelly SM, Scott DP, Safronetz D, Haddock E, LaCasse R, Thomas MJ, Sova P, Carter VS, Weiss JM, Miller DR, Shaw GD, Korth MJ, Heise MT, Baric RS, de Villena FP, Feldmann H, Katze MG (2014) Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance. Science (New York) 346:987–991
83. Roberts A, Paddock C, Vogel L, Butler E, Zaki S, Subbarao K (2005) Aged BALB/c mice as a model for increased severity of severe acute respiratory syndrome in elderly humans. J Virol 79:5833–5838
84. Roberts A, Deming D, Paddock CD, Cheng A, Yount B, Vogel L, Herman BD, Sheahan T, Heise M, Genrich GL, Zaki SR, Baric R, Subbarao K (2007a) A mouse-adapted SARS-coronavirus causes disease and mortality in BALB/c mice. PLoS Pathog 3:e5
85. Roberts A, Pardo-Manuel de Villena F, Wang W, McMillan L, Threadgill DW (2007b) The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics. Mamm Genome 18:473–481
86. Roberts A, Lamirande EW, Vogel L, Jackson JP, Paddock CD, Guarner J, Zaki SR, Sheahan T, Baric R, Subbarao K (2008) Animal models and vaccines for SARS-CoV infection. Virus Res 133:20–32
87. Rockx B, Sheahan T, Donaldson E, Harkema J, Sims A, Heise M, Pickles R, Cameron M, Kelvin D, Baric R (2007) Synthetic reconstruction of zoonotic and early human severe acute respiratory syndrome coronavirus isolates that produce fatal disease in aged mice. J Virol 81:7410–7423
88. Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS (2017) Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 10.1126/scitranslmed.aal3653
89. Subbarao K, McAuliffe J, Vogel L, Fahle G, Fischer S, Tatti K, Packard M, Shieh WJ, Zaki S, Murphy B (2004) Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice. J Virol 78:3572–3577
90. Tai W, Zhao G, Sun S, Guo Y, Wang Y, Tao X, Tseng CK, Li F, Jiang S, Du L, Zhou Y (2016) A recombinant receptor-binding domain of MERS-CoV in trimeric form protects human dipeptidyl peptidase 4 (hDPP4) transgenic mice from MERS-CoV infection. Virology 499:375–382
91. Threadgill DW, Hunter KW, Williams RW (2002) Genetic dissection of complex and quantitative traits: from fantasy to reality via a community effort. Mamm Genome 13:175–178
92. Totura AL, Baric RS (2012) SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Curr Opin Virol 2:264–275
93. Totura AL, Whitmore A, Agnihothram S, Schafer A, Katze MG, Heise MT, Baric RS (2015) Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. mBio 6:e00638-00615
94. Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW (2004) ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem 279:17996–18007
95. Tseng CT, Huang C, Newman P, Wang N, Narayanan K, Watts DM, Makino S, Packard MM, Zaki SR, Chan TS, Peters CJ (2007) Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human angiotensin-converting enzyme 2 virus receptor. J Virol 81:1162–1173
96. Tsui PT, Kwok ML, Yuen H, Lai ST (2003) Severe acute respiratory syndrome: clinical outcome and prognostic correlates. Emerg Infect Dis 9:1064–1069
97. van Doremalen N, Miazgowicz KL, Milne-Price S, Bushmaker T, Robertson S, Scott D, Kinne J, McLellan JS, Zhu J, Munster VJ (2014) Host species restriction of Middle East respiratory syndrome coronavirus through its receptor, dipeptidyl peptidase 4. J Virol 88:9220–9232
98. van Doremalen N, Falzarano D, Ying T, de Wit E, Bushmaker T, Feldmann F, Okumura A, Wang Y, Scott DP, Hanley PW, Feldmann H, Dimitrov DS, Munster VJ (2017) Efficacy of antibody-based therapies against Middle East respiratory syndrome coronavirus (MERS-CoV) in common marmosets. Antivir Res 143:30–37
99. Wang S, Wei M, Han Y, Zhang K, He L, Yang Z, Su B, Zhang Z, Hu Y, Hui W (2008) Roles of TNF-alpha gene polymorphisms in the occurrence and progress of SARS-Cov infection: a case-control study. BMC Infect Dis 8:27
100. Wang N, Shi X, Jiang L, Zhang S, Wang D, Tong P, Guo D, Fu L, Cui Y, Liu X, Arledge KC, Chen YH, Zhang L, Wang X (2013) Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Res 23:986–993
101. Wang Q, Qi J, Yuan Y, Xuan Y, Han P, Wan Y, Ji W, Li Y, Wu Y, Wang J, Iwamoto A, Woo PC, Yuen KY, Yan J, Lu G, Gao GF (2014) Bat origins of MERS-CoV supported by bat coronavirus HKU4 usage of human receptor CD26. Cell Host Microbe 16:328–337
102. Wang L, Shi W, Chappell JD, Joyce MG, Zhang Y, Kanekiyo M, Becker MM, van Doremalen N, Fischer R, Wang N, Corbett KS, Choe M, Mason RD, Van Galen JG, Zhou T, Saunders KO, Tatti KM, Haynes LM, Kwong PD, Modjarrad K, Kong WP, McLellan JS, Denison MR, Munster VJ, Mascola JR, Graham BS (2018) Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on MERS-CoV Spike to avoid neutralization escape. J Virol. 10.1128/JVI.02002-17
103. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, Zamani R, Kenny T, Eaton BP, Grimes E, Welch LS, Gomba L, Wilhelmsen CL, Nichols DK, Nuss JE, Nagle ER, Kugelman JR, Palacios G, Doerffler E, Neville S, Carra E, Clarke MO, Zhang L, Lew W, Ross B, Wang Q, Chun K, Wolfe L, Babusis D, Park Y, Stray KM, Trancheva I, Feng JY, Barauskas O, Xu Y, Wong P, Braun MR, Flint M, McMullan LK, Chen SS, Fearns R, Swaminathan S, Mayers DL, Spiropoulou CF, Lee WA, Nichol ST, Cihlar T, Bavari S (2016) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531:381–385
104. Wu Z, Yang L, Ren X, Zhang J, Yang F, Zhang S, Jin Q (2016) ORF8-related genetic evidence for Chinese horseshoe bats as the source of human severe acute respiratory syndrome coronavirus. J Infect Dis 213:579–583
105. Yang XH, Deng W, Tong Z, Liu YX, Zhang LF, Zhu H, Gao H, Huang L, Liu YL, Ma CM, Xu YF, Ding MX, Deng HK, Qin C (2007) Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection. Comp Med 57:450–459
106. Yang Y, Du L, Liu C, Wang L, Ma C, Tang J, Baric RS, Jiang S, Li F (2014) Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proc Natl Acad Sci USA 111:12516–12521
107. Yang L, Guell M, Niu D, George H, Lesha E, Grishin D, Aach J, Shrock E, Xu W, Poci J, Cortazio R, Wilkinson RA, Fishman JA, Church G (2015) Genome-wide inactivation of porcine endogenous retroviruses (PERVs). Science (New York) 350:1101–1104
108. Yang XL, Hu B, Wang B, Wang MN, Zhang Q, Zhang W, Wu LJ, Ge XY, Zhang YZ, Daszak P, Wang LF, Shi ZL (2016) Isolation and characterization of a novel bat coronavirus closely related to the direct progenitor of severe acute respiratory syndrome coronavirus. J Virol 90:3253–3256
109. Yuan Y, Cao D, Zhang Y, Ma J, Qi J, Wang Q, Lu G, Wu Y, Yan J, Shi Y, Zhang X, Gao GF (2017) Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains. Nat Commun 8:15092
110. Zhao J, Wohlford-Lenane C, Zhao J, Fleming E, Lane TE, McCray PB Jr, Perlman S (2012) Intranasal treatment with poly(I*C) protects aged mice from lethal respiratory virus infections. J Virol 86:11416–11424
111. Zhao J, Li K, Wohlford-Lenane C, Agnihothram SS, Fett C, Zhao J, Gale MJ Jr, Baric RS, Enjuanes L, Gallagher T, McCray PB Jr, Perlman S (2014) Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci USA 111:4970–4975
112. Zhao G, Jiang Y, Qiu H, Gao T, Zeng Y, Guo Y, Yu H, Li J, Kou Z, Du L, Tan W, Jiang S, Sun S, Zhou Y (2015) Multi-organ damage in human dipeptidyl peptidase 4 transgenic mice infected with Middle East respiratory syndrome-coronavirus. PLoS ONE 10:e0145561
113. Zhou J, To KK, Dong H, Cheng ZS, Lau CC, Poon VK, Fan YH, Song YQ, Tse H, Chan KH, Zheng BJ, Zhao GP, Yuen KY (2012) A functional variation in CD55 increases the severity of 2009 pandemic H1N1 influenza A virus infection. J Infect Dis 206:495–503
114. Zhou P, Fan H, Lan T, Yang XL, Shi WF, Zhang W, Zhu Y, Zhang YW, Xie QM, Mani S, Zheng XS, Li B, Li JM, Guo H, Pei GQ, An XP, Chen JW, Zhou L, Mai KJ, Wu ZX, Li D, Anderson DE, Zhang LB, Li SY, Mi ZQ, He TT, Cong F, Guo PJ, Huang R, Luo Y, Liu XL, Chen J, Huang Y, Sun Q, Zhang XL, Wang YY, Xing SZ, Chen YS, Sun Y, Li J, Daszak P, Wang LF, Shi ZL, Tong YG, Ma JY (2018) Fatal swine acute diarrhoea syndrome caused by an HKU2-related coronavirus of bat origin. Nature 556:255–258
115. Zhu X, Wang Y, Zhang H, Liu X, Chen T, Yang R, Shi Y, Cao W, Li P, Ma Q, Zhai Y, He F, Zhou G, Cao C (2011) Genetic variation of the human alpha-2-Heremans-Schmid glycoprotein (AHSG) gene associated with the risk of SARS-CoV infection. PLoS ONE 6:e23730
116. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY (2016) Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov 15:327–347