Liu Tianxu, Cao Yalei, Weng Jiaming, Gao Songzhan, Jin Zirun, Zhang Yun, Yang Yuzhuo, Zhang He, Xia Changyou, Yin Xin, Luo Yong, He Qiyu, Jiang Hui, Wang Lin, Zhang Zhe
Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
Department of Urology, Peking University Third Hospital, Beijing, People's Republic of China.
Emerg Microbes Infect. 2024 Dec;13(1):2332657. doi: 10.1080/22221751.2024.2332657. Epub 2024 Apr 27.
Globally, hepatitis E virus (HEV) infections are prevalent. The finding of high viral loads and persistent viral shedding in ejaculate suggests that HEV replicates within the human male genital tract, but its target organ is unknown and appropriate models are lacking. We aimed to determine the HEV tropism in the human testis and its potential influence on male reproductive health. We conducted an ex vivo culture of human testis explants and in vitro culture of primary human Sertoli cells. Clinically derived HEV genotype 1 (HEV1) and HEV3 virions, as well as rat-derived HEV-C1, were used for inoculation. Transcriptomic analysis was performed on testis tissues collected from tacrolimus-treated rabbits with chronic HEV3 infection. Our findings reveal that HEV3, but not HEV1 or HEV-C1, can replicate in human testis explants and primary human Sertoli cells. Tacrolimus treatment significantly enhanced the replication efficiency of HEV3 in testis explants and enabled successful HEV1 infection in Sertoli cells. HEV3 infection disrupted the secretion of several soluble factors and altered the cytokine microenvironment within primary human Sertoli cells. Finally, intratesticular transcriptomic analysis of immunocompromised rabbits with chronic HEV infection indicated downregulation of genes associated with spermatogenesis. HEV can infect the human testicular tissues and Sertoli cells, with increased replication efficiency when exposed to tacrolimus treatment. These findings shed light on how HEV may persist in the ejaculate of patients with chronic hepatitis E and provide valuable ex vivo tools for studying countermeasures.
在全球范围内，戊型肝炎病毒（HEV）感染普遍存在。在精液中发现高病毒载量和持续病毒脱落表明HEV在人类男性生殖道内复制，但其靶器官尚不清楚且缺乏合适的模型。我们旨在确定HEV在人类睾丸中的嗜性及其对男性生殖健康的潜在影响。我们进行了人类睾丸外植体的体外培养和原代人类支持细胞的体外培养。使用临床来源的HEV基因型1（HEV1）和HEV3病毒粒子以及大鼠来源的HEV-C1进行接种。对从慢性HEV3感染的他克莫司治疗兔收集的睾丸组织进行转录组分析。我们的研究结果表明，HEV3而非HEV1或HEV-C1可在人类睾丸外植体和原代人类支持细胞中复制。他克莫司治疗显著提高了HEV3在睾丸外植体中的复制效率，并使支持细胞成功感染HEV1。HEV3感染破坏了几种可溶性因子的分泌，并改变了原代人类支持细胞内的细胞因子微环境。最后，对慢性HEV感染的免疫受损兔的睾丸内转录组分析表明与精子发生相关的基因下调。HEV可感染人类睾丸组织和支持细胞，在接受他克莫司治疗时复制效率增加。这些发现揭示了HEV如何在慢性戊型肝炎患者的精液中持续存在，并为研究应对措施提供了有价值的体外工具。
