寨卡病毒感染、雄性橄榄狒狒生殖器官靶向和精液传播。

Zika Virus Infection, Reproductive Organ Targeting, and Semen Transmission in the Male Olive Baboon.

机构信息

Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Section of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

出版信息

J Virol. 2019 Dec 12;94(1). doi: 10.1128/JVI.01434-19.

Abstract

Zika virus (ZIKV) infection in pregnant women is a serious threat to the development and viability of the fetus. The primary mode of ZIKV transmission to humans is through mosquito bites, but sexual transmission has also been well documented in humans. However, little is known of the short- and long-term effects of ZIKV infection on the human male reproductive system. This study examines the effects of ZIKV infection on the male reproductive organs and semen and the immune response of the olive baboon (). Nine mature male baboons were infected with ZIKV (French Polynesian strain) subcutaneously. Six animals were euthanized at 41 days, while three animals were euthanized at 10 or 11 days postinfection (dpi). Viremia and clinical evidence of infection were present in all nine baboons. ZIKV RNA was present in the semen of five of nine baboons. ZIKV was present in the testes of two of three males euthanized at 10 or 11 dpi, but in none of six males at 41 dpi. Immunofluorescence of testes suggested the presence of ZIKV in sperm progenitor cells, macrophage penetration of seminiferous tubules, and increased tumor necrosis factor alpha (TNF-α), particularly in vascular walls. These data demonstrate that male olive baboons approximate the male human ZIKV response, including viremia, the adaptive immune response, and persistent ZIKV in semen. Although gross testicular pathology was not seen, the demonstrated breach of the testes-blood barrier and targeting of spermatogenic precursors suggest possible long-term implications in ZIKV-infected primates. Zika virus (ZIKV) is an emerging flavivirus spread through mosquitoes and sexual contact. ZIKV infection during pregnancy can lead to severe fetal outcomes, including miscarriage, fetal death, preterm birth, intrauterine growth restriction, and fetal microcephaly, collectively known as congenital Zika syndrome. Therefore, it is important to understand how this virus spreads, as well as the resulting pathogenesis in translational animal models that faithfully mimic ZIKV infection in humans. Such models will contribute to the future development of efficient therapeutics and prevention mechanisms. Through our previous work in olive baboons, we developed a nonhuman primate model that is permissive to ZIKV infection and transfers the virus vertically from mother to fetus, modeling human observations. The present study contributes to understanding of ZIKV infection in male baboon reproductive tissues and begins to elucidate how this may affect fertility, reproductive capacity, and sexual transmission of the virus.

摘要

Zika 病毒(ZIKV)感染孕妇对胎儿的发育和生存能力构成严重威胁。ZIKV 向人类传播的主要途径是通过蚊子叮咬,但也有充分的证据表明性传播也是人类感染 ZIKV 的途径。然而,人们对 ZIKV 感染对人类男性生殖系统的短期和长期影响知之甚少。本研究探讨了 ZIKV 感染对雄性生殖器官和精液的影响,以及雄性橄榄狨猴()的免疫反应。将 9 只成熟雄性狨猴皮下感染 ZIKV(法属波利尼西亚株)。6 只动物在 41 天处死,3 只动物在感染后 10 或 11 天处死。9 只狨猴均出现病毒血症和感染的临床证据。9 只狨猴中有 5 只的精液中存在 ZIKV RNA。在感染后 10 或 11 天处死的 3 只雄性狨猴中有 2 只的睾丸中存在 ZIKV,但在感染后 41 天处死的 6 只雄性狨猴中没有发现 ZIKV。睾丸的免疫荧光显示 ZIKV 存在于精子祖细胞、巨噬细胞穿透曲细精管和肿瘤坏死因子-α(TNF-α)增加,特别是在血管壁中。这些数据表明,雄性橄榄狨猴近似于人类的 ZIKV 反应,包括病毒血症、适应性免疫反应和精液中持续存在的 ZIKV。虽然没有发现明显的睾丸病理学改变,但睾丸-血液屏障的破坏和生精前体细胞的靶向表明,在感染 ZIKV 的灵长类动物中可能存在长期影响。Zika 病毒(ZIKV)是一种通过蚊子和性接触传播的新兴黄病毒。孕妇感染 ZIKV 可导致严重的胎儿结局,包括流产、胎儿死亡、早产、宫内生长受限和胎儿小头畸形,统称为先天性 Zika 综合征。因此,了解这种病毒的传播方式以及在能够真实模拟人类 ZIKV 感染的转化动物模型中导致的发病机制非常重要。这种模型将有助于未来开发有效的治疗和预防机制。通过我们之前在橄榄狨猴中的研究,我们开发了一种允许 ZIKV 感染的非人类灵长类动物模型,并从母亲垂直传递病毒给胎儿,模拟了人类的观察结果。本研究有助于了解 ZIKV 感染雄性狨猴生殖组织的情况,并开始阐明这可能如何影响生育能力、生殖能力和病毒的性传播。

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