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In this study, we show that the secretion of ORF8 is dependent on its N\u2010terminal signal peptide sequence and can be inhibited by reactive oxygen species scavenger and endoplasmic reticulum\u2010Golgi transportation inhibitor in cultured cells. To trace the effect of its possible in vivo secretion, we examined the plasma samples of coronavirus disease 2019\u00a0(COVID\u201019)\u00a0convalescent patients and found that the patients aged from 40 to 60 had higher antibody titers than those under 40. To explore ORF8's in vivo function, we administered the mice with ORF8 via tail\u2010vein injection to simulate the circulating ORF8 in the patient. Although no apparent difference in body weight, food intake, and vitality was detected between vehicle\u2010 and ORF8\u2010treated mice, the latter displayed morphological abnormalities of testes and epididymides, as indicated by the loss of the central ductal lumen accompanied by a decreased fertility in 5\u2010week\u2010old male mice. Furthermore, the analysis of gene expression in the testes between vehicle\u2010 and ORF8\u2010treated mice identified a decreased expression of Col1a1, the loss of which is known to be associated with mice's infertility. Although whether our observation in mice could be translated to humans remains unclear, our study provides a potential mouse model that can be used to investigate the impact of severe acute respiratory syndrome coronavirus 2\u00a0(SARS\u2010CoV\u20102) infection on the human reproductive system.<\/jats:p>","DOI":"10.1002\/jmv.27855","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T03:43:32Z","timestamp":1652672612000},"page":"4193-4205","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["ORF8 protein of SARS\u2010CoV\u20102 reduces male fertility in mice"],"prefix":"10.1002","volume":"94","author":[{"given":"Ting","family":"Yu","sequence":"first","affiliation":[{"name":"The Center for Infection and Immunity Study and Molecular Cancer Research Center, School of Medicine Sun Yat\u2010sen University  Shenzhen Guangdong 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