Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California, USA.
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
J Virol. 2020 Apr 16;94(9). doi: 10.1128/JVI.00067-20.
Zika virus (ZIKV) is a major human pathogen. ZIKV can replicate in female and male reproductive organs, thus facilitating the human-human transmission cycle. Viral shedding in the semen can increase the risk of ZIKV transmission through sexual mode. Therefore, the vaginal and anorectal mucosa are relevant sites for ZIKV infection. However, the pathobiology of ZIKV transmission through the rectal route is not well understood. Here, we utilize a mouse model system to investigate the immunopathological consequences following ZIKV infection of the rectal mucosa compared to a subcutaneous route of infection. We show that ZIKV-rectal inoculation results in viremia with subclinical infection. ZIKV infects the mucosal epithelium and submucosal dendritic cells, inducing immune and inflammatory cell infiltration. Rectal transmission of ZIKV resulted in the generation of serum-neutralizing antibody responses. Mass cytometry analyses of splenocytes showed a significantly reduced level of inflammatory monocyte and neutrophil cellular responses in the rectal route group. Furthermore, immunological priming through the rectal mucosa with an attenuated ZIKV strain resulted in significant protection from lethal subcutaneous ZIKV challenge, further eliciting robust memory CD4-positive (CD4) and CD8 T-cell and ZIKV-specific serum-neutralizing antibody responses. Thus, our study provides deeper immunopathobiological insights on rectal transmission and highlights a rational strategy for mucosal immunization. This model system recapitulates clinical aspects of human ZIKV disease outcome, where most infections are well controlled and result in subclinical and asymptomatic outcomes. Zika virus is a clinically significant human pathogen that is primarily transmitted and spread by species mosquitoes but is also sexually transmissible. The recent pandemic in the Americas led to an unprecedented increase of newborn babies with developmental brain and eye abnormalities. To date, there is no licensed vaccine or therapeutic intervention available for the fight against ZIKV. Understanding the sexual transmission of ZIKV through vaginal and rectal routes is necessary to restrict virus transmission and spread. This study examines the early immunological and pathological consequences of rectal and subcutaneous routes of ZIKV infection using a mouse model. We characterized the primary target cells of ZIKV infection and the subsequent mucosal immune responses to infection, and we demonstrate the protective effect of mucosal rectal immunization using an attenuated ZIKV strain. This mucosal vaccination approach can be further developed to prevent future ZIKV outbreaks.
Zika 病毒（ZIKV）是一种主要的人类病原体。ZIKV 可以在女性和男性生殖器官中复制，从而促进人与人之间的传播周期。精液中的病毒脱落会增加通过性模式传播 ZIKV 的风险。因此，阴道和肛门直肠黏膜是 ZIKV 感染的相关部位。然而，ZIKV 通过直肠途径传播的病理生物学尚不清楚。在这里，我们利用小鼠模型系统研究了 ZIKV 感染直肠黏膜与皮下感染途径相比后的免疫病理后果。我们表明，ZIKV-直肠接种会导致亚临床感染的病毒血症。ZIKV 感染黏膜上皮和黏膜下树突状细胞，诱导免疫和炎症细胞浸润。ZIKV 通过直肠传播会产生血清中和抗体反应。脾细胞的质谱细胞分析显示，直肠途径组的炎症性单核细胞和中性粒细胞细胞反应水平显著降低。此外，通过直肠黏膜用减毒 ZIKV 株进行免疫接种可显著保护免受致命的皮下 ZIKV 攻击，进一步引发强烈的记忆 CD4 阳性（CD4）和 CD8 T 细胞和 ZIKV 特异性血清中和抗体反应。因此，我们的研究提供了对直肠传播的更深层次的免疫病理生物学见解，并强调了黏膜免疫接种的合理策略。该模型系统再现了人类 ZIKV 疾病结果的临床方面，其中大多数感染得到很好的控制，导致亚临床和无症状的结果。Zika 病毒是一种具有临床意义的人类病原体，主要通过 种蚊子传播和传播，但也具有性传播能力。最近在美洲的大流行导致患有发育中大脑和眼睛异常的新生儿数量空前增加。迄今为止，尚无针对 ZIKV 的许可疫苗或治疗干预措施。了解 ZIKV 通过阴道和直肠途径的性传播对于限制病毒传播和扩散是必要的。本研究使用小鼠模型检查了 ZIKV 皮下和直肠感染途径的早期免疫和病理后果。我们描述了 ZIKV 感染的主要靶细胞以及随后对感染的黏膜免疫反应，并使用减毒 ZIKV 株证明了黏膜直肠免疫接种的保护作用。这种黏膜接种方法可以进一步开发，以防止未来的 ZIKV 爆发。
