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http://dx.doi.org/10.4014/jmb.1910.10055

Middle East Respiratory Syndrome-Coronavirus Infection into Established hDPP4-Transgenic Mice Accelerates Lung Damage Via Activation of the Pro-Inflammatory Response and Pulmonary Fibrosis  

Kim, Ju (Department of Molecular Biology and the Institute for Molecular Biology and Genetics, Jeonbuk National University)
Yang, Ye Lin (Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Jeonbuk National University)
Jeong, Yongsu (Graduate School of Biotechnology, Kyung Hee University)
Jang, Yong-Suk (Department of Molecular Biology and the Institute for Molecular Biology and Genetics, Jeonbuk National University)
Publication Information
Journal of Microbiology and Biotechnology / v.30, no.3, 2020 , pp. 427-438 More about this Journal
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) infects the lower respiratory airway of humans, leading to severe acute respiratory failure. Unlike human dipeptidyl peptidase 4 (hDPP4), a receptor for MERS-CoV, mouse DPP4 (mDPP4) failed to support MERS-CoV infection. Consequently, diverse transgenic mouse models expressing hDPP4 have been developed using diverse methods, although some models show no mortality and/or only transient and mild-to-moderate clinical signs following MERS-CoV infection. Additionally, overexpressed hDPP4 is associated with neurological complications and breeding difficulties in some transgenic mice, resulting in impeding further studies. Here, we generated stable hDPP4-transgenic mice that were sufficiently susceptible to MERS-CoV infection. The transgenic mice showed weight loss, decreased pulmonary function, and increased mortality with minimal perturbation of overexpressed hDPP4 after MERS-CoV infection. In addition, we observed histopathological signs indicative of progressive pulmonary fibrosis, including thickened alveolar septa, infiltration of inflammatory monocytes, and macrophage polarization as well as elevated expression of profibrotic molecules and acute inflammatory response in the lung of MERS-CoV-infected hDPP4-transgenic mice. Collectively, we suggest that this hDPP4-transgenic mouse is useful in understanding the pathogenesis of MERS-CoV infection and for antiviral research and vaccine development against the virus.
Keywords
Animal model; hDPP4; MERS-CoV; pathogenesis; transgenic mouse;
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1 Pardo A, Gibson K, Cisneros J, Richards TJ, Yang Y, Becerril C, et al. 2005. Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. PLoS Med. 2: e251.   DOI
2 Borthwick LA, Wynn TA, Fisher AJ. 2013. Cytokine mediated tissue fibrosis. Biochim. Biophys. Acta. 1832: 1049-1060.   DOI
3 Pascal KE, Coleman CM, Mujica AO, Kamat V, Badithe A, Fairhurst J, et al. 2015. Pre- and postexposure effi- cacy 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.   DOI
4 Cockrell AS, Yount BL, Scobey T, Jensen K, Douglas M, Beall A, et al. 2016. A mouse model for MERS coronavirus induced acute respiratory distress syndrome. Nat. Microbiol. 2: 16226.   DOI
5 Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, et al. 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.   DOI
6 Laksitorini M, Prasasty VD, Kiptoo PK, Siahaan TJ. 2014. Pathways and progress in improving drug delivery through the intestinal mucosa and blood-brain barriers. Ther. Deliv. 5: 1143-1163.   DOI
7 Crystal RG, Bitterman PB, Mossman B, Schwarz MI, Sheppard D, Almasy L, et al. 2002. Future research directions in idiopathic pulmonary fibrosis: summary of a national heart, lung, and blood institute working group. Am. J. Respir. Crit. Care Med. 166: 236-246.   DOI
8 Takasawa W, Ohnuma K, Hatano R, Endo Y, Dang NH, Morimoto C. 2010. Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines. Biochem. Biophys. Res. Commun. 401: 7-12.   DOI
9 Garrett WS, Gordon JI, Glimcher LH. 2010. Homeostasis and inflammation in the intestine. Cell 140: 859-870.   DOI
10 Aich P, Wilson HL, Kaushik RS, Potter AA, Babiuk LA, Griebel P. 2007. Comparative analysis of innate immune responses following infection of newborn calves with bovine rotavirus and bovine coronavirus. J. Gen. Virol. 88: 2749-2761.   DOI
11 Gordon S, Martinez FO. 2010. Alternative activation of macrophages: mechanism and functions. Immunity 32: 593-604.   DOI
12 Eom J, Yoo J, Kim JJ, Lee JB, Choi W, Park CG, et al. 2018. Viperin deficiency promotes polarization of macrophages and secretion of M1 and M2 cytokines. Immun. Netw. 18: e32.   DOI
13 de Wit E, Rasmussen AL, Falzarano D, Bushmaker T, Feldmann F, Brining DL, et al. 2013. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc. Natl. Acad. Sci. USA 110: 16598-6603.   DOI
14 Braga TT, Agudelo JS, Camara NO. 2015. Macrophages during the fibrotic process: M2 as friend and foe. Front. Immunol. 6: 602.
15 Conway B, Hughes J. 2012. Cellular orchestrators of renal fibrosis. QJM 105: 611-615.   DOI
16 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.   DOI
17 Scobey T, Yount BL, Sims AC, Donaldson EF, Agnihothram SS, Men- achery VD, et al. 2013. Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus. Proc. Natl. Acad. Sci. USA 110: 16157-16162.   DOI
18 Cockrell AS, Peck KM, Yount BL, Agnihothram SS, Scobey T, Curnes NR, et al. 2014. Mouse d ipeptidyl p ep tidase 4 is not a functional receptor for Middle East respiratory syndrome coronavirus infection. J. Virol. 88: 5195-5199.   DOI
19 Falzarano D, de Wit E, Feldmann F, Rasmussen AL, Okumura A, Peng X, et al. 2014. Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog. 10: e1004250.   DOI
20 Zhao J, Li K, Wohlford-Lenane C, Agnihothram SS, Fett C, Gale MJ, et al. 2014. Rapid generation of a mouse model for Middle East respiratory syndrome. Proc. Natl. Acad. Sci. USA 111: 4970-4975.   DOI
21 Zhao G, Jiang Y, Qiu H, Gao T, Zeng Y, Guo Y, et al. 2015. Multi-Organ damage in human dipeptidyl peptidase 4 transgenic mice infected with Middle East respiratory syndrome-coronavirus. PLoS One 10: e0145561.   DOI
22 Agrawal AS, Garron T, Tao X, Peng BH, Wakamiya M, Chan TS, et al. 2015. Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J. Virol. 89: 3659-3670.   DOI
23 van Doremalen N, Miazgowicz KL, Milne-Price S, Bushmaker T, Robertson S, Scott D, et al. 2014. Host species restriction of Middle East respiratory syndrome coronavirus through its receptor, dipeptidyl peptidase 4. J. Virol. 88: 220-9232.
24 WHO MERS-CoV Research Group. 2013. State of knowledge and data gaps of Middle East respiratory syndrome coronavirus (MERS-CoV) in humans. PLoS Curr. 5: currents. outbreaks.0bf719e352e7478f8ad85fa30127ddb8.
25 Lee JY, Bae S, Myoung J. 2019. Generation of full-length infectious cDNA clones of middle east respiratory syndrome coronavirus. J. Microbiol. Biotechnol. 29: 999-1007.   DOI
26 Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, et al. 2013. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495: 51-254.   DOI
27 Boonacker E, Van Noorden CJ. 2003. The multifunctional or moonlighting protein CD26/DPPIV. Eur. J. Cell Biol. 82: 53-73.   DOI
28 Mackay IM, Arden KE. 2015. Middle East respiratory syndrome: An emerging coronavirus infection tracked by the crowd. Virus Res. 202: 60-88.   DOI
29 Coleman CM, Matthews KL, Goicochea L, Frieman MB. 2013. Wild type and innate immune deficient mice are not susceptible to the middle east respiratory syndrome coronavirus. J. Gen. Virol. 95: 408-412.   DOI
30 Mu J, Petrov A, Eiermann GJ, Woods J, Zhou YP, Li Z, et al. 2009. Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur. J. Pharmacol. 623: 148-154.   DOI
31 Tseng CT, Tseng J, Perrone L, Worthy M, Popov V, Peters CJ. 2005. A pical entry and release of severe acute respiratory syndrome-associated coronavirus in polarized Calu-3 lung epithelial cells. J. Virol. 79: 9470-9479.   DOI
32 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.   DOI
33 Reed M, Morris SH, Owczarczyk AB, Lukacs NW. 2015. Deficiency of autophagy protein Map1-LC3b mediates IL-17-dependent lung pathology during respiratory viral infection via ER stress-associated IL-1. Mucosal. Immunol 8: 1118-1130.   DOI
34 Wilson MS, Wynn TA. 2009 Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal. Immunol. 2: 103-121.   DOI
35 Wynn, T. A. 2008. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214: 199-210.   DOI
36 Kim J, Yang YL, Jang YS. 2019. Human ${\beta}$-defensin 2 is involved in CCR2-mediated Nod2 signal transduction, leading to activation of the innate immune response in macrophages. Immunobiology 224: 502-510.   DOI
37 Lee JY, Bae S, Myoung J. 2019. Middle East respiratory syndrome coronavirus-encoded accessory proteins impair MDA5-and TBK1-mediated activation of NF-${\kappa}B$. J. Microbiol. Biotechnol. 29: 1316-1323.   DOI
38 Raj VS, Smits SL, Provacia LB, van den Brand JM, Wiersma L, Ou- wendijk WJ, et al. 2014. Aden- osine deaminase acts as a natural antagonist for dipeptidyl peptidase 4-mediated entry of the Middle East respiratory syndrome coronavirus. J. Virol. 88: 1834-1838.   DOI
39 de Wit E, Prescott J, Baseler L, Bushmaker T, Thomas T, Lackemeyer MG, et al. 2013. The Middle East respiratory syndrome coronavirus (MERS-CoV) does not replicate in Syrian hamsters. PLoS One 8: e69127.   DOI
40 Zhou J, Chu H, Li C, Wong BH, Cheng ZS, Poon VK, et al. 2014. Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis. J. Infect. Dis. 209: 1331-1342.   DOI
41 Tilbury K, Hocker J, Wen BL, Sandbo N, Singh V, Campagnola PJ. 2014. Second harmonic generation microscopy analysis of extracellular matrix changes in human idiopathic pulmonary fibrosis. J. Biomed. Opt. 19: 086014.   DOI
42 Li K, Zhong B. 2018. Regulation of cellular antiviral signaling by modifications of ubiquitin and ubiquitin-like molecules. Immune. Netw. 18: e4.   DOI
43 Tseng CT, Huang C, Newman P, Wang N, Narayanan K, Watts DM, et al. 2007. Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human Angiotensin-converting enzyme 2 virus receptor. J. Virol. 81: 1162-1173.   DOI
44 Yoshikawa N, Yoshikawa T, Hill T, Huang C, Watts DM, Makino S, et al. 2009. Differential virological and immunological outcome of severe acute respiratory syndrome coronavirus infection in susceptible and resistant transgenic mice expressing human angiotensin-converting enzyme 2. J. Virol 83: 5451-5465.   DOI
45 Wong SL, Sukkar MB. 2017. The SPARC protein an overview o f its role i n lung c ancer and p ulmonary f ibrosis and its potential role in chronic airways disease. Br. J. Pharmacol. 174: 3-14.   DOI