Infection of SARS-CoV-2 causes severe pathological changes in mouse testis

Min Chen; Shihua Li; Shujun Liu; Yuhang Zhang; Xiuhong Cui; Limin Lv; Bowen Liu; Aihua Zheng; Qihui Wang; Shuguang Duo; Fei Gao

doi:10.1016/j.jgg.2022.11.011

Volume 50 Issue 2

Feb. 2023

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2023 > 50(2): 99-107

PDF( 6953 KB)

Infection of SARS-CoV-2 causes severe pathological changes in mouse testis

doi: 10.1016/j.jgg.2022.11.011

a. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
b. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China;
c. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China;
d. University of Chinese Academy of Sciences, Beijing 100101, China;
e. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China;
f. Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
g. State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
h. CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing 100101, China

Funds:

D program of China (2018YFA0107700), the National Natural Science Foundation of China (32170855, 31970785), and Biological Resources Program of Chinese Academy of Sciences (KFJ-BRP-005).

We appreciate the staff of the biosafety level 3 (BSL3) laboratory in the institute of Microbiology, Chinese Academy of Sciences. This work was supported by National key R&

Received Date: 2022-09-28
Accepted Date: 2022-11-23
Rev Recd Date: 2022-11-23
Publish Date: 2022-12-06

Abstract

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than 600 million people worldwide. Several organs including lung, intestine, and brain are infected by SARS-CoV-2. It has been reported that SARS-CoV-2 receptor angiotensin-converting enzyme-2 (ACE2) is expressed in human testis. However, whether testis is also affected by SARS-CoV-2 is still unclear. In this study, we generate a human ACE2 (hACE2) transgenic mouse model in which the expression of hACE2 gene is regulated by hACE2 promoter. Sertoli and Leydig cells from hACE2 transgenic mice can be infected by SARS-CoV-2 pseudovirus in vitro, and severe pathological changes are observed after injecting the SARS-CoV-2 pseudovirus into the seminiferous tubules. Further studies reveal that Sertoli and Leydig cells from hACE2 transgenic mice are also infected by authentic SARS-CoV-2 virus in vitro. After testis interstitium injection, authentic SARS-CoV-2 viruses are first disseminated to the interstitial cells, and then detected inside the seminiferous tubules which in turn cause germ cell loss and disruption of seminiferous tubules. Our study demonstrates that testis is most likely a target of SARS-CoV-2 virus. Attention should be paid to the reproductive function in SARS-CoV-2 patients.
- SARS-CoV-2,
- ACE2,
- Sertoli cell,
- Leydig cell,
- Testis

FullText(HTML)

References(37)

References

Bao, L., Deng, W., Huang, B., Gao, H., Liu, J., Ren, L., Wei, Q., Yu, P., Xu, Y., Qi, F., et al., 2020. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature, 583, 830-833

Campos, R. K., Camargos, V. N., Azar, S. R., Haines, C. A., Eyzaguirre, E. J. Rossi, S. L., 2021. SARS-CoV-2 Infects Hamster Testes. Microorganisms, 9, 1318

Chen, M., Dong, F., Chen, M., Shen, Z., Wu, H., Cen, C., Cui, X., Bao, S. Gao, F., 2021. PRMT5 regulates ovarian follicle development by facilitating Wt1 translation. Elife, 10, e68930

Chen, M., Wang, X., Wang, Y., Zhang, L., Xu, B., Lv, L., Cui, X., Li, W. Gao, F., 2014. Wt1 is involved in leydig cell steroid hormone biosynthesis by regulating paracrine factor expression in mice. Biol. Reprod, 90, 71

Chen, M., Zhang, L., Cui, X., Lin, X., Li, Y., Wang, Y., Wang, Y., Qin, Y., Chen, D., Han, C., et al., 2017. Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression. Development, 144, 44-53

Clarke, N.E, Turner, A.J., 2012. Angiotensin-converting enzyme 2: the first decade. Int. J. Hypertens, 2012, 307315

Douglas, G. C., O'Bryan, M. K., Hedger, M. P., Lee, D. K., Yarski, M. A., Smith, A. I. Lew, R. A., 2004. The novel angiotensin-converting enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. Endocrinology, 145, 4703-4711

Gonzalez, D. C., Khodamoradi, K., Pai, R., Guarch, K., Connelly, Z. M., Ibrahim, E., Arora, H., Ramasamy, R., 2020. A Systematic Review on the Investigation of SARS-CoV-2 in Semen. Res. Rep. Urol., 12, 615-621

Guo, L., Zhao, S., Li, W., Wang, Y., Li, L., Jiang, S., Ren, W., Yuan, Q., Zhang, F., Kong, F., et al., 2021. Absence of SARS-CoV-2 in semen of a COVID-19 patient cohort. Andrology, 9, 42-47

Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N. H., Nitsche, A., et al., 2020. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181, 271-280

Holtmann, N., Edimiris, P., Andree, M., Doehmen, C., Baston-Buest, D., Adams, O., Kruessel, J. S., Bielfeld, A. P., 2020. Assessment of SARS-CoV-2 in human semen-a cohort study. Fertil Steril, 114, 233-238

Jiang, R. D., Liu, M. Q., Chen, Y., Shan, C., Zhou, Y. W., Shen, X. R., Li, Q., Zhang, L., Zhu, Y., Si, H. R., et al., 2020. Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2. Cell, 182, 50-58

Kayaaslan, B., Korukluoglu, G., Hasanoglu, I., Kalem, A. K., Eser, F., Akinci, E., Guner, R., 2020. Investigation of SARS-CoV-2 in Semen of Patients in the Acute Stage of COVID-19 Infection. Urol. Int., 104, 678-683

Li, C., Ye, Z., Zhang, A. J., Chan, J. F., Song, W., Liu, F., Chen, Y., Kwan, M. Y., Lee, A. C., Zhao, Y., et al., 2022a. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections by intranasal or testicular inoculation induces testicular damage preventable by vaccination in golden Syrian hamsters. Clin. Infect. Dis. 75, e974-e990

Li, D., Jin, M., Bao, P., Zhao, W. and Zhang, S., 2020b. Clinical characteristics and results of semen tests among men with coronavirus disease 2019. JAMA Netw. Open, 3, e208292

Li, H., Zhao, C., Zhang, Y., Yuan, F., Zhang, Q., Shi, X., Zhang, L., Qin, C., Zheng, A., 2020c. Establishment of replication-competent vesicular stomatitis virus-based recombinant viruses suitable for SARS-CoV-2 entry and neutralization assays. Emerg. Microbes Infect., 9, 2269-2277

Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., Ren, R., Leung, K. S. M., Lau, E. H. Y., Wong, J. Y., et al., 2020d. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med., 382, 1199-1207

Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., et al., 2020. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet, 395, 565-574

Ma, L., Xie, W., Li, D., Shi, L., Ye, G., Mao, Y., Xiong, Y., Sun, H., Zheng, F., Chen, Z., et al., 2021. Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. J. Med. Virol., 93, 456-462

Moshrefi, M., Ghasemi-Esmailabad, S., Ali, J., Findikli, N., Mangoli, E., Khalili, M. A., 2021. The probable destructive mechanisms behind COVID-19 on male reproduction system and fertility. J. Assist. Reprod. Genet., 38, 1691-1708

Munoz-Fontela, C., Dowling, W. E., Funnell, S. G. P., Gsell, P. S., Riveros-Balta, A. X., Albrecht, R. A., Andersen, H., Baric, R. S., Carroll, M. W., Cavaleri, M., et al., 2020. Animal models for COVID-19. Nature, 586, 509-515

Omolaoye, T. S., Adeniji, A. A., Cardona Maya, W. D. and du Plessis, S. S., 2021. SARS-COV-2 (Covid-19) and male fertility: Where are we? Reprod Toxicol., 99, 65-70

Pan, F., Xiao, X., Guo, J., Song, Y., Li, H., Patel, D. P., Spivak, A. M., Alukal, J. P., Zhang, X., Xiong, C., et al., 2020. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril., 113, 1135-1139

Paoli, D., Pallotti, F., Colangelo, S., Basilico, F., Mazzuti, L., Turriziani, O., Antonelli, G., Lenzi, A. and Lombardo, F., 2020. Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab. J. Endocrinol. Invest., 43, 1819-1822

Peng, L., Liu, J., Xu, W., Luo, Q., Chen, D., Lei, Z., Huang, Z., Li, X., Deng, K., Lin, B., et al., 2020. SARS-CoV-2 can be detected in urine, blood, anal swabs, and oropharyngeal swabs specimens. J Med. Virol., 92, 1676-1680

Rathnasinghe, R., Strohmeier, S., Amanat, F., Gillespie, V. L., Krammer, F., Garcia-Sastre, A., Coughlan, L., Schotsaert, M. and Uccellini, M. B., 2020. Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection. Emerg. Microbes Infect, 9, 2433-2445

Rawlings, S. A., Ignacio, C., Porrachia, M., Du, P., Smith, D. M., Chaillon, A., 2020. No Evidence of SARS-CoV-2 seminal shedding despite SARS-CoV-2 persistence in the upper respiratory tract. Open Forum. Infect. Dis., 7, ofaa325

Seymen, C. M., 2021. The other side of COVID-19 pandemic: Effects on male fertility. J. Med. Virol., 93, 1396-1402

Sheikhzadeh Hesari, F., Hosseinzadeh, S.S., Asl Monadi Sardroud, M.A., 2021. Review of COVID-19 and male genital tract. Andrologia, 53, e13914

Song, C., Wang, Y., Li, W., Hu, B., Chen, G., Xia, P., Wang, W., Li, C., Diao, F., Hu, Z., et al., 2020. Absence of 2019 novel coronavirus in semen and testes of COVID-19 patientsdagger. Biol. Reprod, 103, 4-6

Sun, S. H., Chen, Q., Gu, H. J., Yang, G., Wang, Y. X., Huang, X. Y., Liu, S. S., Zhang, N. N., Li, X. F., Xiong, R., et al., 2020. A mouse model of SARS-CoV-2 infection and pathogenesis. Cell Host Microbe, 28, 124-133

Wang, W., Xu, Y., Gao, R., Lu, R., Han, K., Wu, G., Tan, W., 2020. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA, 323, 1843-1844

Wang, Z. and Xu, X., 2020. scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, leydig and sertoli cells. Cells, 9, 920

Yang, M., Chen, S., Huang, B., Zhong, J. M., Su, H., Chen, Y. J., Cao, Q., Ma, L., He, J., Li, X. F., et al., 2020. Pathological findings in the testes of COVID-19 patients: clinical implications. Eur. Urol. Focus, 6, 1124-1129

Younis, J. S., Abassi, Z., Skorecki, K., 2020. Is there an impact of the COVID-19 pandemic on male fertility? The ACE2 connection. Am. J. Physiol. Endocrinol. Metab., 318, E878-E880

Zhou, P., Yang, X. L., Wang, X. G., Hu, B., Zhang, L., Zhang, W., Si, H. R., Zhu, Y., Li, B., Huang, C. L., et al., 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579, 270-273

Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., et al., 2020. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med., 382, 727-733

Relative Articles

Supplements(0)

Cited By

Proportional views