Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

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)
  • Received : 2019.10.28
  • Accepted : 2019.12.14
  • Published : 2020.03.28
Download PDF
⟨ Previous Next ⟩

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

References

  1. 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.
  2. 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. https://doi.org/10.4014/jmb.0905.05061
  3. 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. https://doi.org/10.1038/495051a
  4. 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.
  5. Boonacker E, Van Noorden CJ. 2003. The multifunctional or moonlighting protein CD26/DPPIV. Eur. J. Cell Biol. 82: 53-73. https://doi.org/10.1078/0171-9335-00302
  6. Mackay IM, Arden KE. 2015. Middle East respiratory syndrome: An emerging coronavirus infection tracked by the crowd. Virus Res. 202: 60-88. https://doi.org/10.1016/j.virusres.2015.01.021
  7. 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. https://doi.org/10.1099/vir.0.060640-0
  8. 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. https://doi.org/10.1128/JVI.02935-13
  9. 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. https://doi.org/10.1371/journal.pone.0069127
  10. 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. https://doi.org/10.1099/vir.0.060640-0
  11. 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. https://doi.org/10.1073/pnas.1311542110
  12. 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. https://doi.org/10.1128/JVI.03764-13
  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. https://doi.org/10.1073/pnas.1310744110
  14. 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. https://doi.org/10.1371/journal.ppat.1004250
  15. 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. https://doi.org/10.1073/pnas.1323279111
  16. 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. https://doi.org/10.1371/journal.pone.0145561
  17. 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. https://doi.org/10.1128/JVI.03427-14
  18. 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. https://doi.org/10.1016/j.ejphar.2009.09.027
  19. 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. https://doi.org/10.1128/JVI.79.15.9470-9479.2005
  20. 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. https://doi.org/10.1016/j.it.2008.02.010
  21. 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. https://doi.org/10.1038/mi.2015.3
  22. Wilson MS, Wynn TA. 2009 Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal. Immunol. 2: 103-121. https://doi.org/10.1038/mi.2008.85
  23. Wynn, T. A. 2008. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214: 199-210. https://doi.org/10.1002/path.2277
  24. 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. https://doi.org/10.1016/j.imbio.2019.05.004
  25. 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. https://doi.org/10.1093/infdis/jit504
  26. 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. https://doi.org/10.4014/jmb.1908.08004
  27. Li K, Zhong B. 2018. Regulation of cellular antiviral signaling by modifications of ubiquitin and ubiquitin-like molecules. Immune. Netw. 18: e4. https://doi.org/10.4110/in.2018.18.e4
  28. 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. https://doi.org/10.1128/JVI.01702-06
  29. 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. https://doi.org/10.1128/JVI.02272-08
  30. 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. https://doi.org/10.1117/1.JBO.19.8.086014
  31. 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. https://doi.org/10.1111/bph.13653
  32. 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. https://doi.org/10.1371/journal.pmed.0020251
  33. Borthwick LA, Wynn TA, Fisher AJ. 2013. Cytokine mediated tissue fibrosis. Biochim. Biophys. Acta. 1832: 1049-1060. https://doi.org/10.1016/j.bbadis.2012.09.014
  34. 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. https://doi.org/10.1073/pnas.1510830112
  35. 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. https://doi.org/10.1038/nmicrobiol.2016.226
  36. 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. https://doi.org/10.1093/infdis/jiv499
  37. 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. https://doi.org/10.4155/tde.14.67
  38. 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. https://doi.org/10.1016/j.bbrc.2010.08.112
  39. Garrett WS, Gordon JI, Glimcher LH. 2010. Homeostasis and inflammation in the intestine. Cell 140: 859-870. https://doi.org/10.1016/j.cell.2010.01.023
  40. 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. https://doi.org/10.1099/vir.0.82861-0
  41. 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. https://doi.org/10.1164/rccm.2201069
  42. Gordon S, Martinez FO. 2010. Alternative activation of macrophages: mechanism and functions. Immunity 32: 593-604. https://doi.org/10.1016/j.immuni.2010.05.007
  43. 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. https://doi.org/10.4110/in.2018.18.e32
  44. Braga TT, Agudelo JS, Camara NO. 2015. Macrophages during the fibrotic process: M2 as friend and foe. Front. Immunol. 6: 602.
  45. Conway B, Hughes J. 2012. Cellular orchestrators of renal fibrosis. QJM 105: 611-615. https://doi.org/10.1093/qjmed/hcr235

Cited by

  1. COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection? vol.12, pp.8, 2020, https://doi.org/10.18632/aging.103001
  2. SARS-CoV-2 and DPP4 inhibition: Is it time to pray for Janus Bifrons? vol.163, 2020, https://doi.org/10.1016/j.diabres.2020.108162
  3. Distribution of ACE2, CD147, CD26, and other SARS‐CoV‐2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID‐19 risk fa vol.75, pp.11, 2020, https://doi.org/10.1111/all.14429
  4. Clinical Symptoms and Types of Samples Are Critical Factors for the Molecular Diagnosis of Symptomatic COVID-19 Patients: A Systematic Literature Review vol.2021, 2020, https://doi.org/10.1155/2021/5528786
  5. D-Limonene Is a Potential Monoterpene to Inhibit PI3K/Akt/IKK-α/NF-κB p65 Signaling Pathway in Coronavirus Disease 2019 Pulmonary Fibrosis vol.8, 2021, https://doi.org/10.3389/fmed.2021.591830
  6. Immunotherapy of multisystem inflammatory syndrome in children (MIS-C) following COVID-19 through mesenchymal stem cells vol.101, pp.no.pb, 2020, https://doi.org/10.1016/j.intimp.2021.108217
  7. Virus infection induced pulmonary fibrosis vol.19, pp.1, 2020, https://doi.org/10.1186/s12967-021-03159-9