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.IMPORTANCE Zika virus is a clinically significant human pathogen that is primarily transmitted and spread by Aedes 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.

中文翻译：

---

寨卡病毒粘膜感染提供保护性免疫。


寨卡病毒（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寨卡病毒通过性行为传播的风险。因此，阴道和肛门直肠粘膜是ZIKV感染的相关部位。然而，ZIKV 通过直肠途径传播的病理学尚不清楚。在这里，我们利用小鼠模型系统来研究直肠粘膜 ZIKV 感染与皮下感染途径相比的免疫病理学后果。我们发现直肠接种 ZIKV 会导致亚临床感染的病毒血症。 ZIKV 感染粘膜上皮和粘膜下树突状细胞，诱导免疫和炎症细胞浸润。 ZIKV 的直肠传播导致血清中和抗体反应的产生。脾细胞的质谱流式分析显示，直肠途径组的炎症单核细胞和中性粒细胞反应水平显着降低。此外，用减毒 ZIKV 毒株通过直肠粘膜进行免疫启动，可显着防止致命的皮下 ZIKV 攻击，进一步引发强大的记忆 CD4 阳性 (CD4+) 和 CD8+ T 细胞以及 ZIKV 特异性血清中和抗体反应。因此，我们的研究提供了关于直肠传播的更深入的免疫病理生物学见解，并强调了粘膜免疫的合理策略。该模型系统概括了人类 ZIKV 疾病结果的临床方面，其中大多数感染得到了很好的控制，并导致亚临床和无症状的结果。重要性 寨卡病毒是一种具有临床意义的人类病原体，主要通过伊蚊传播和传播，但也可以通过性传播。最近美洲的大流行导致患有大脑和眼睛发育异常的新生儿数量空前增加。迄今为止，还没有获得许可的疫苗或治疗干预措施可用于对抗 ZIKV。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传播至关重要。本研究使用小鼠模型研究了 ZIKV 直肠和皮下途径感染的早期免疫学和病理学后果。我们表征了 ZIKV 感染的主要靶细胞以及随后对感染的粘膜免疫反应，并证明了使用减毒 ZIKV 毒株进行粘膜直肠免疫的保护作用。这种粘膜疫苗接种方法可以进一步发展，以预防未来 ZIKV 的爆发。