ORF8 protein of SARS-CoV-2 reduces male fertility in mice

Ting Yu, Qiao Ling, Mengxin Xu, Niu Wang, Lixia Wang, Hanwen Lin, Manqi Cao, Yong Ma, Yuanyuan Wang, Kuibiao Li, Liubing Du, Yunyun Jin, Ying Li, Deyin Guo, Xiaoxue Peng, Yao-qing Chen, Bo Zhao, Ji-An Pan

The Center for Infection and Immunity Study and Molecular Cancer Research Center, School of Medicine, Sun Yat‐sen University, Shenzhen, Guangdong, China; School of Public Health (Shenzhen), Sun Yat‐sen University, Shenzhen, Guangdong, China; Guangzhou Center for Diseases Control and Prevention, Guangzhou, Guangdong, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat‐sen University, Guangzhou, China

Abstract: As one of the most rapidly evolving proteins of the genus Betacoronavirus, open reading frames (ORF8’s) function and potential pathological consequence in vivo are still obscure. In this study, we show that the secretion of ORF8 is dependent on its N-terminal signal peptide sequence and can be inhibited by reactive oxygen species scavenger and endoplasmic reticulum-Golgi transportation inhibitor in cultured cells. To trace the effect of its possible in vivo secretion, we examined the plasma samples of coronavirus disease 2019 (COVID-19) convalescent 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-vein injection to simulate the circulating ORF8 in the patient. Although no apparent difference in body weight, food intake, and vitality was detected between vehicle- and ORF8-treated 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-week-old male mice. Furthermore, the analysis of gene expression in the testes between vehicle- and ORF8-treated 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 (SARS-CoV-2) infection on the human reproductive system.

J Med Virol. 2022;1–13. – https://doi.org/10.1002/jmv.27855
Received: 27 April 2022 | Accepted: 10 May 2022 | First published: 15 May 2022