Vulnerability of The Male Reproductive System to SARS-CoV-2 Invasion: Potential Role for The Endoplasmic Reticulum Chaperone Grp78/HSPA5/BiP

Document Type : Review Article

Authors

1 Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran

2 Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada

3 Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

4 Department of Physiology, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Malaysia

5 School of Natural Medicine, Faculty of Community and Health Sciences, University of the Western Cape, Cape Town, South Africa

6 Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt

7 Ajyal IVF Center, Ajyal Hospital, Sohag, Egypt

8 American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may adversely affect male reproductive tissues and male
fertility. This concern is elicited by the higher susceptibility and mortality rate of men to the SARS-CoV-2 mediated coronavirus disease-19 (COVID-19), compared to the women. SARS-CoV-2 enters host cells after binding to a functional receptor named angiotensin-converting enzyme-2 (ACE2) and then replicates in the host cells and gets released into the plasma. SARS-CoVs use the endoplasmic reticulum (ER) as a site for viral protein synthesis and processing, as well as glucose-regulated protein 78 (Grp78) is a key ER chaperone involved in protein folding by preventing newly synthesized proteins from aggregation.
Therefore, we analyzed Grp78 expression in various human organs, particularly male reproductive organs, using Broad
Institute Cancer Cell Line Encyclopedia (CCLE), the Genotype-Tissue Expression (GTEx), and Human Protein Atlas online
datasets. Grp78 is expressed in male reproductive tissues such as the testis, epididymis, prostate, and seminal vesicle. It can facilitate the coronavirus entry into the male reproductive tract, providing an opportunity for its replication. This link between the SARS-CoV-2 and the Grp78 protein could become a therapeutic target to mitigate its harmful effects on male fertility.

Keywords

References

1. Zanke AA, Thenge RR, Adhao VS. COVID-19: A pandemic declare by world health organization. IP Int J Compr Adv Pharmacol. 2020; 5(2): 49-57.
2. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020; 20(5): 533-534.
3. Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020; 368: m606.
4. Teixeira TA, Bernardes FS, Oliveira YC, Hsieh MK, Esteves SC, Duarte Neto AN, et al. SARS-CoV-2 and multi-organ damage–what men’s health specialists should know about the COVID-19 pathophysiology. Int Braz J Urol. 2021; 47(3): 637-646.
5. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020; 181(2): 271-280.
6. Abdel-Moneim A. COVID-19 pandemic and male fertility: Clinical manifestations and pathogenic mechanisms. Biochemistry (Mosc). 2021; 86(4): 389-396.
7. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020; 395(10224): 565-574.
8. Wang Z, Xu X. 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. 2020; 9(4): 920.
9. Tian Y, Zhou LQ. Evaluating the impact of COVID-19 on male reproduction. Reproduction. 2021; 161(2): R37-R44.
10. Stopsack KH, Mucci LA, Antonarakis ES, Nelson PS, Kantoff PW. TMPRSS2 and COVID-19: Serendipity or opportunity for intervention? Cancer Discov. 2020; 10(6): 779-782.
11. Hallak J, Teixeira TA, Bernardes FS, Carneiro F, Duarte SA, Pariz JR, et al. SARS-CoV-2 and its relationship with the genitourinary tract: Implications for male reproductive health in the context of COVID-19 pandemic. Andrology. 2021; 9(1):73-79.
12. Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002; 417(6891): 822-828.
13. Yagil Y, Yagil C. Hypothesis: ACE2 modulates blood pressure in the mammalian organism. Hypertension. 2003; 41: 871–873.
14. Hezavehei M, Shokoohian B, Nasr-Esfahani MH, Shpichka A, Timashev P, Shahverdi AH, et al. Possible male reproduction complications after coronavirus pandemic. Cell J. 2021; 23(4): 382-388.
15. Tabar AN, Sojoudi K, Henduei H, Azizi H. Review of sertoli cell dysfunction caused by COVID-19 that could affect male fertility. Zygote. 2021; 30(1): 17-24.
16. Lee W, Mok A, Chung JP. Potential effects of COVID-19 on reproductive systems and fertility; assisted reproductive technology guidelines and considerations: a review. Hong Kong Med J. 2021; 27: 118-126.
17. Edenfield RC, Easley CA. Implications of testicular ACE2 and the renin–angiotensin system for SARS-CoV-2 on testis function. Nat Rev Urol. 2022; 19(2): 116-127.
18. Valdivia A, Cortés L, Beitia M, Totorikaguena L, Agirregoitia N, Corcostegui B, et al. Role of angiotensin-(1–7) via MAS receptor in human sperm motility and acrosome reaction. Reprod. 2020; 159(3): 241-249.
19. Aitken RJ. COVID-19 and human spermatozoa-Potential risks for infertility and sexual transmission? Andrology. 2021; 9(1): 48-52.
20. Agarwal A, Saleh RA, Bedaiwy MA. Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril. 2003; 79(4): 829-843.
21. Roychoudhury S, Das A, Sengupta P, Dutta S, Roychoudhury S, Choudhury AP, et al. Viral pandemics of the last four decades: pathophysiology, health impacts and perspectives. Int J Environ Res Public Health. 2020; 17(24): 9411.
22. Schuppe HC, Meinhardt A, Allam JP, Bergmann M, Weidner W, Haidl G. Chronic orchitis: a neglected cause of male infertility? Andrologia. 2008; 40(2): 84-91.
23. Mahé D, Matusali G, Deleage C, Alvarenga RL, Satie AP, Pagliuzza A, et al. Potential for virus endogenization in humans through testicular germ cell infection: the case of HIV. J Virol. 2020; 94(24): e01145-20.
24. Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, et al. Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod. 2006; 74(2): 410-416.
25. Yao Y, Yuan X, Wu L, Guo N, Yin L, Li Y. COVID-19 and male reproduction: Current research and unknown factors. Andrology. 2021; 9(4): 1027-1037.
26. Khalili MA, Leisegang K, Majzoub A, Finelli R, Selvam MK, Henkel R, et al. Male fertility and the COVID-19 pandemic: systematic review of the literature. World J Mens Health. 2020; 38(4): 506-520.
27. Rastrelli G, Di Stasi V, Inglese F, Beccaria M, Garuti M, Di Costanzo D, et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology. 2021; 9(1): 88-98.
28. Almanza A, Carlesso A, Chintha C, Creedican S, Doultsinos D, Leuzzi B, et al. Endoplasmic reticulum stress signalling–from basic mechanisms to clinical applications. FEBS J. 2019; 286(2): 241-278.
29. Ibrahim IM, Abdelmalek DH, Elfiky AA. GRP78: a cell’s response to stress. Life Sci. 2019; 226: 156-163.
30. Karna KK, Shin YS, Choi BR, Kim HK, Park JK. The role of endoplasmic reticulum stress response in male reproductive physiology and pathology: a review. World J Mens Health. 2020; 38(4): 484-494.
31. Casas C. GRP78 at the centre of the stage in cancer and neuroprotection. Front Neurosci. 2017; 11: 177.
32. Ni M, Zhang Y, Lee AS. Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochem J. 2011; 434(2): 181-188.
33. Xing X, Lai M, Wang Y, Xu E, Huang Q. Overexpression of glucose- regulated protein 78 in colon cancer. Clin Chim Acta. 2006; 364(1-2): 308-315.
34. Boilard M, Reyes-Moreno C, Lachance C, Massicotte L, Bailey JL, Sirard MA, et al. Localization of the chaperone proteins GRP78 and HSP60 on the luminal surface of bovine oviduct epithelial cells and their association with spermatozoa. Biol Reprod. 2004; 71(6): 1879-1889.
35. Lachance C, Bailey JL, Leclerc P. Expression of Hsp60 and Grp78 in the human endometrium and oviduct, and their effect on sperm functions. Hum Reprod. 2007; 22(10): 2606-2614.
36. Booth L, Roberts JL, Cash DR, Tavallai S, Jean S, Fidanza A, et al. GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease. J Cell Physiol. 2015; 230(7): 1661-1676.
37. Turpin J, Frumence E, Harrabi W, Haddad JG, El Kalamouni C, Desprès P, et al. Zika virus subversion of chaperone GRP78/BiP expression in A549 cells during UPR activation. Biochimie. 2020; 175: 99-105.
38. Chu H, Chan CM, Zhang X, Wang Y, Yuan S, Zhou J, et al. Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells. J Biol Chem. 2018; 293(30): 11709-11726.
39. Carlos AJ, Ha DP, Yeh DW, Van Krieken R, Tseng CC, Zhang P, et al. The chaperone GRP78 is a host auxiliary factor for SARSCoV- 2 and GRP78 depleting antibody blocks viral entry and infection. J Biol Chem. 2021: 296: 100759.
40. Ibrahim IM, Abdelmalek DH, Elshahat ME, Elfiky AA. COVID-19 spike-host cell receptor GRP78 binding site prediction. J Infect. 2020; 80(5): 554-562.
41. Chan CP, Siu KL, Chin KT, Yuen KY, Zheng B, Jin DY. Modulation of the unfolded protein response by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2006; 80(18): 9279- 9287.
42. Elgohary AM, Elfiky AA, Barakat K. GRP78: A possible relationship of COVID-19 and the mucormycosis; in silico perspective. Comput Biol Med. 2021; 139: 104956.
43. Jindadamrongwech S, Thepparit C, Smith DR. Identification of GRP 78 (BiP) as a liver cell expressed receptor element for dengue virus serotype 2. Arch Virol. 2004; 149(5): 915-927.
44. Honda T, Horie M, Daito T, Ikuta K, Tomonaga K. Molecular chaperone BiP interacts with Borna disease virus glycoprotein at the cell surface. J Virol. 2009; 83(23): 12622-12625.
45. Elfiky AA. SARS-CoV-2 spike-heat shock protein A5 (GRP78) recognition may be related to the immersed human coronaviruses. Front Pharmacol. 2020; 11: 577467.
46. Sabirli R, Koseler A, Goren T, Turkcuer I, Kurt O. High GRP78 levels in Covid-19 infection: a case-control study. Life Sci. 2021; 265: 118781.
47. Kim Y, Lillo AM, Steiniger SC, Liu Y, Ballatore C, Anichini A, et al. Targeting heat shock proteins on cancer cells: selection, characterization, and cell-penetrating properties of a peptidic GRP78 ligand. Biochemistry. 2006; 45(31): 9434-9444.
48. Yoneda Y, Steiniger SC, Čapková K, Mee JM, Liu Y, Kaufmann GF, et al. A cell-penetrating peptidic GRP78 ligand for tumor cell-specific prodrug therapy. Bio Med Chem Lett. 2008; 18(5): 1632-1636.
49. Huo R, Zhu YF, Ma X, Lin M, Zhou ZM, Sha JH. Differential expression of glucose-regulated protein 78 during spermatogenesis. Cell Tissue Res. 2004; 316(3): 359-367.
50. Aguilar-Mahecha A, Hales BF, Robaire B. Expression of stress response genes in germ cells during spermatogenesis. Biol Reprod. 2001; 65(1): 119-127.
51. Wang W, Wang X, Zhu P, Sun CM, Jin S, Liu J, et al. Expression and location of glucose-regulated protein 78 in testis and epididymis. WIMJ Open. 2014; 1: 14-7.
52. Rahmani M, Tavalaee M, Hosseini M, Eskandari A, Shaygannia E, Sadeghi N, et al. Deferasirox, an iron-chelating agent, improves testicular morphometric and sperm functional parameters in a pat model of varicocele. Oxid Med Cell Longev. 2021; 2021: 6698482.
53. Yesudhas D, Srivastava A, Gromiha MM. COVID-19 outbreak: history, mechanism, transmission, structural studies and therapeutics. Infection. 2021; 49(2): 199-213.
54. Song C, Wang Y, Li W, Hu B, Chen G, Xia P, et al. Absence of 2019 novel coronavirus in semen and testes of COVID-19 patients. Biol Reprod. 2020; 103(1): 4-6.
55. Pan F, Xiao X, Guo J, Song Y, Li H, Patel DP, et al. No evidence of severe acute respiratory syndrome–coronavirus 2 in semen of males recovering from coronavirus disease 2019. Ferti Steril. 2020; 113(6): 1135-1139.
56. Ma L, Xie W, Li D, Shi L, Ye G, Mao Y, et al. Evaluation of sexelated hormones and semen characteristics in reproductive-aged male COVID-19 patients. J Med Virol. 2021; 93(1):456-462.
57. Stanley KE, Thomas E, Leaver M, Wells D. Coronavirus disease-19 and fertility: viral host entry protein expression in male and female reproductive tissues. Fertil Steril. 2020; 114(1):33-43.
58. Luo S, Baumeister P, Yang S, Abcouwer SF, Lee AS. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through an upstream ATF/CRE site independent of the endoplasmic reticulum stress elements. J Biol Chem. 2003; 278(39): 37375-37385.
59. Guzel E, Arlier S, Guzeloglu-Kayisli O, Tabak MS, Ekiz T, Semerci N, et al. Endoplasmic reticulum stress and homeostasis in reproductive physiology and pathology. Int J Mol Sci. 2017; 18(4): 792.
60. Hebert-Schuster M, Rotta BE, Kirkpatrick B, Guibourdenche J, Cohen M. The interplay between glucose-regulated protein 78 (GRP78) and steroids in the reproductive system. Int J Mol Sci. 2018; 19(7): 1842.
61. Gifford JB, Huang W, Zeleniak AE, Hindoyan A, Wu H, Donahue TR, et al. Expression of GRP78, master regulator of the unfolded protein response, increases chemoresistance in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2016; 15(5): 1043-1052.
62. Rasche L, Duell J, Morgner C, Chatterjee M, Hensel F, Rosenwald A, et al. The natural human IgM antibody PAT-SM6 induces apoptosis in primary human multiple myeloma cells by targeting heat shock protein GRP78. PLoS One. 2013; 8(5): e63414.
63. Lee AS. Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer. 2014; 14(4): 263-276.
64. Ferrara F, Staquicini DI, Driessen WH, D’Angelo S, Dobroff AS, Barry M, et al. Targeted molecular-genetic imaging and liganddirected therapy in aggressive variant prostate cancer. Proc Natl Acad Sci USA. 2016; 113(45): 12786-12791.
65. Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020; 21(3): 335-337.
66. Gosain R, Abdou Y, Singh A, Rana N, Puzanov I, Ernstoff MS. COVID-19 and cancer: a comprehensive review. Curr Oncol Rep. 2020; 22(5): 1-5.
67. Toyoda Y, Akarlar B, Sarov M, Ozlu N, Saitoh S. Extracellular glucose level regulates dependence on GRP 78 for cell surface localization of multipass transmembrane proteins in HeLa cells. FEBS lett. 2018; 592(19): 3295-3304.
68. Girona J, Rodríguez-Borjabad C, Ibarretxe D, Vallvé JC, Ferré R, Heras M, et al. The circulating GRP78/BiP is a marker of metabolic diseases and atherosclerosis: bringing endoplasmic reticulum stress into the clinical scenario. J Clin Med. 2019; 8(11):1793.
69. Santos A, Magro DO, Evangelista-Poderoso R, Saad MJ. Diabetes, obesity, and insulin resistance in COVID-19: molecular interrelationship and therapeutic implications. Diabetol Metab Syndr. 2021; 13(1): 23.
70. Verma S, Saksena S, Sadri-Ardekani H. ACE2 receptor expression in testes: implications in coronavirus disease 2019 pathogenesis. Biol Reprod. 2020; 103(3): 449-451.

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