DOI QR코드

DOI QR Code

Effect of severe acute respiratory syndrome coronavirus 2 infection during pregnancy in K18-hACE2 transgenic mice

  • Byeongseok, Kim (Department of Stem Cell and Regenerative Biotechnology, Konkuk University) ;
  • Ki Hoon, Park (Department of Research and Development, KR BIOTECH CO., Ltd.) ;
  • Ok-Hee, Lee (Department of Veterinary Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Giwan, Lee (Department of Stem Cell and Regenerative Biotechnology, Konkuk University) ;
  • Hyukjung, Kim (Department of Stem Cell and Regenerative Biotechnology, Konkuk University) ;
  • Siyoung, Lee (Department of Stem Cell and Regenerative Biotechnology, Konkuk University) ;
  • Semi, Hwang (Department of Stem Cell and Regenerative Biotechnology, Konkuk University) ;
  • Young Bong, Kim (Department of Biomedical Science and Engineering, Konkuk University) ;
  • Youngsok, Choi (Department of Stem Cell and Regenerative Biotechnology, Konkuk University)
  • 투고 : 2022.04.08
  • 심사 : 2022.08.06
  • 발행 : 2023.01.01

초록

Objective: This study aimed to examine the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on pregnancy in cytokeratin-18 (K18)-hACE2 transgenic mice. Methods: To determine the expression of hACE2 mRNA in the female reproductive tract of K18-hACE2 mice, real-time polymerase chain reaction (RT-PCR) was performed using the ovary, oviduct, uterus, umbilical cord, and placenta. SARS-CoV-2 was inoculated intranasally (30 μL/mouse, 1×104 TCID50/mL) to plug-checked K18-hACE2 homozygous female mice at the pre-and post-implantation stages at 2.5 days post-coitum (dpc) and 15.5 dpc, respectively. The number of implantation sites was checked at 7.5 dpc, and the number of normally born pups was investigated at 20.5 dpc. Pregnancy outcomes, including implantation and childbirth, were confirmed by comparison with the non-infected group. Tissues of infected mice were collected at 7.5 dpc and 19.5 dpc to confirm the SARS-CoV-2 infection. The infection was identified by performing RT-PCR on the infected tissues and comparing them to the non-infected tissues. Results: hACE2 mRNA expression was confirmed in the female reproductive tract of the K18-hACE2 mice. Compared to the non-infected group, no significant difference in the number of implantation sites or normally born pups was found in the infected group. SARS-CoV-2 infection was detected in the lungs but not in the female reproductive system of infected K18-hACE2 mice. Conclusion: In K18-hACE2 mice, intranasal infection with SARS-CoV-2 did not induce implantation failure, preterm labor, or miscarriage. Although the viral infection was not detected in the uterus, placenta, or fetus, the infection of the lungs could induce problems in the reproductive system. However, lung infections were not related to pregnancy outcomes.

키워드

과제정보

We would like to thank Editage (www.editage.co.kr) for English language editing.

참고문헌

  1. Coronavirus Disease (COVDI-19) dashboard [Internet]. Geneva, Switzerland: World-Health-Organization; c2022 [cited 2022 March10]. Available from: https://covid19.who.int 
  2. Chmielewska B, Barratt I, Townsend R, et al. Effects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis. Lancet Glob Health 2021;9:e759-e72. https://doi.org/10.1016/s2214-109x(21)00079-6 
  3. Ziegler CGK, Allon SJ, Nyquist SK, et al. SARS-CoV-2 Receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 2020;181:1016-35.e19. https://doi.org/10.1016/j.cell.2020.04.035 
  4. Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Med J Aust 2020;213:54-6.e1. https://doi.org/10.5694/mja2.50674 
  5. Oladunni FS, Park JG, Pino PA, et al. Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice. Nat Commun 2020;11:6122. https://doi.org/10.1038/s41467-020-19891-7 
  6. Gheblawi M, Wang K, Viveiros A, et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res 2020;126:1456-74. https://doi.org/10.1161/circresaha.120.317015 
  7. Ashary N, Bhide A, Chakraborty P, et al. Single-Cell RNA-seq identifies cell subsets in human placenta that highly expresses factors driving pathogenesis of SARS-CoV-2. Front Cell Dev Biol 2020;8:783. https://doi.org/10.3389/fcell.2020.00783 
  8. Parry S, Holder J, Strauss JF, 3rd. Mechanisms of trophoblastvirus interaction. J Reprod Immunol 1997;37:25-34. https://doi.org/10.1016/s0165-0378(97)00071-5 
  9. Koi H, Zhang J, Makrigiannakis A, et al. Syncytiotrophoblast is a barrier to maternal-fetal transmission of herpes simplex virus. Biol Reprod 2002;67:1572-9. https://doi.org/10.1095/biolreprod.102.004325 
  10. Arora N, Sadovsky Y, Dermody TS, Coyne CB. Microbial Vertical transmission during human pregnancy. Cell Host Microbe 2017;21:561-7. https://doi.org/10.1016/j.chom.2017.04.007 
  11. Stegmann BJ, Carey JC. TORCH infections. toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus (CMV), and herpes infections. Curr Womens Health Rep 2002;2:253-8. 
  12. Coyne CB, Lazear HM. Zika virus - reigniting the TORCH. Nat Rev Microbiol 2016;14:707-15. https://doi.org/10.1038/nrmicro.2016.125 
  13. Miner JJ, Cao B, Govero J, et al. Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell 2016;165:1081-91. https://doi.org/10.1016/j.cell.2016.05.008 
  14. Szaba FM, Tighe M, Kummer LW, et al. Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection. PLoS Pathog 2018;14:e1006994. https://doi.org/10.1371/journal.ppat.1006994 
  15. Hosier H, Farhadian SF, Morotti RA, et al. SARS-CoV-2 infection of the placenta. J Clin Invest 2020;130:4947-53. https://doi.org/10.1172/jci139569 
  16. Juan J, Gil MM, Rong Z, Zhang Y, Yang H, Poon LC. Effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: systematic review. Ultrasound Obstet Gynecol 2020;56:15-27. https://doi.org/10.1002/uog.22088 
  17. Song D, Prahl M, Gaw SL, et al. Passive and active immunity in infants born to mothers with SARS-CoV-2 infection during pregnancy: Prospective cohort study. BMJ Open 2021;11:e053036. https://doi.org/10.1136/bmjopen-2021-053036 
  18. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://doi.org/10.1016/s0140-6736(20)30183-5 
  19. McCray PB, Jr., Pewe L, Wohlford-Lenane C, et al. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol 2007;81:813-21. https://doi.org/10.1128/jvi.02012-06 
  20. Mendoza EJ, Manguiat K, Wood H, Drebot M. Two detailed plaque assay protocols for the quantification of infectious SARS-CoV-2. Curr Protoc Microbiol 2020;57:e105. https://doi.org/10.1002/cpmc.105 
  21. Brandolini M, Taddei F, Marino MM, et al. Correlating qRTPCR, dPCR and viral titration for the identification and quantification of SARS-CoV-2: a new approach for infection management. Viruses 2021;13:1022. https://doi.org/10.3390/v13061022 
  22. Wilhelm A, Pallas C, Marschalek R, Widera M. Detection and quantification of SARS-CoV-2 by Real-Time RT-PCR assay. In: Chu JJH, Ahidjo BA, Mok CK, editors. SARS-CoV-2. Methods in molecular biology. New York, NY, USA: Humana; 2022. vol 2452. https://doi.org/10.1007/978-1-0716-2111-0_6 
  23. Jing Y, Run-Qian L, Hao-Ran W, et al. Potential influence of COVID-19/ACE2 on the female reproductive system. Mol Hum Reprod 2020;26:367-73. https://doi.org/10.1093/molehr/gaaa030 
  24. Dong W, Mead H, Tian L, et al. The K18-Human ACE2 transgenic mouse model recapitulates non-severe and severe COVID-19 in response to an infectious dose of the SARSCoV-2 virus. J Virol 2022;96:e00964-21. https://doi.org/10.1128/jvi.00964-21 
  25. Liu Y, Sawalha AH, Lu Q. COVID-19 and autoimmune diseases. Curr Opin Rheumatol 2021;33:155-62. https://doi.org/10.1097/bor.0000000000000776 
  26. Zhu G, Du S, Wang Y, et al. Delayed antiviral immune responses in severe acute respiratory syndrome coronavirus infected pregnant mice. Front Microbiol 2022;12:806902. https://doi.org/10.3389/fmicb.2021.806902 
  27. Winkler ES, Bailey AL, Kafai NM, et al. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat Immunol 2020;21:1327-35. https://doi.org/10.1038/s41590-020-0778-2 
  28. Gao L, Ren J, Xu L, et al. Placental pathology of the third trimester pregnant women from COVID-19. Diagn Pathol 2021;16:8. https://doi.org/10.1186/s13000-021-01067-6 
  29. Penfield CA, Brubaker SG, Limaye MA, et al. Detection of severe acute respiratory syndrome coronavirus 2 in placental and fetal membrane samples. Am J Obstet Gynecol MFM 2020;2:100133. https://doi.org/10.1016/j.ajogmf.2020.100133 
  30. Cribiu FM, Erra R, Pugni L, et al. Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission. J Clin Invest 2021;131:e145427. https://doi.org/10.1172/jci145427 
  31. Vivanti AJ, Vauloup-Fellous C, Prevot S, et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun 2020;11:3572. https://doi.org/10.1038/s41467-020-17436-6 
  32. Alzamora MC, Paredes T, Caceres D, Webb CM, Valdez LM, Rosa ML. Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol 2020;37:861-5. https://doi.org/10.1055/s-0040-1710050 
  33. Mayhew TM. Taking tissue samples from the placenta: an illustration of principles and strategies. Placenta 2008;29:1-14. https://doi.org/10.1016/j.placenta.2007.05.010 
  34. Weatherbee BAT, Glover DM, Zernicka-Goetz M. Expression of SARS-CoV-2 receptor ACE2 and the protease TMPRSS2 suggests susceptibility of the human embryo in the first trimester. Open Biol 2020;10:200162. https://doi.org/10.1098/rsob.200162 
  35. Carossino M, Kenney D, O'Connell AK, et al. Fatal Neurodissemination and SARS-CoV-2 tropism in K18-hACE2 mice is only partially dependent on hACE2 expression. Viruses 2022;14:535. https://doi.org/10.3390/v14030535 
  36. Cuffe JS, Walton SL, Steane SE, Singh RR, Simmons DG, Moritz KM. The effects of gestational age and maternal hypoxia on the placental renin angiotensin system in the mouse. Placenta 2014;35:953-61. https://doi.org/10.1016/j.placenta.2014.09.004 
  37. Cui D, Liu Y, Jiang X, et al. Single-cell RNA expression profiling of SARS-CoV-2-related ACE2 and TMPRSS2 in human trophectoderm and placenta. Ultrasound Obstet Gynecol 2021;57:248-56. https://doi.org/10.1002/uog.22186 
  38. Cardenas I, Means RE, Aldo P, et al. Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol 2010;185:1248-57. https://doi.org/10.4049/jimmunol.1000289 
  39. Chudnovets A, Liu J, Narasimhan H, Liu Y, Burd I. Role of inflammation in virus pathogenesis during pregnancy. J Virol 2020;95:e01381-19. https://doi.org/10.1128/jvi.01381-19