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：

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寨卡病毒粘膜感染可提供保护性免疫。

寨卡病毒（ZIKV）是主要的人类病原体。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，阴道和肛门直肠粘膜是ZIKV感染的相关部位。但是，ZIKV通过直肠途径传播的病理生物学尚未得到很好的了解。在这里，我们利用小鼠模型系统来研究与皮下感染途径相比，直肠黏膜ZIKV感染后的免疫病理后果。我们显示ZIKV直肠接种可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，诱导免疫和炎性细胞浸润。ZIKV的直肠传播导致血清中和抗体反应的产生。脾细胞的大量细胞计数分析表明，在直肠途径组中，炎性单核细胞和中性粒细胞的反应明显降低。此外，通过减毒的ZIKV菌株通过直肠粘膜的免疫学引发对致命的皮下ZIKV攻击产生了显着的保护作用，进一步引发了记忆力强的CD4阳性（CD4 +）和CD8 + T细胞以及ZIKV特异性的血清中和抗体反应。因此，我们的研究为直肠传播提供了更深入的免疫病理学见解，并突出了黏膜免疫的合理策略。该模型系统概括了人类ZIKV疾病结局的临床方面，重要信息寨卡病毒是一种临床上重要的人类病原体，主要由伊蚊（Aedes）蚊子传播和传播，但也可以通过性传播。美洲最近的大流行导致具有发育性脑部和眼睛异常的新生婴儿数量空前增加。迄今为止，尚无可用于对抗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的传播和传播是必要的。这项研究使用小鼠模型检查了ZIKV感染的直肠和皮下途径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，并且我们证明了使用减毒的ZIKV株进行粘膜直肠免疫的保护作用。可以进一步开发这种粘膜疫苗接种方法，以防止未来的ZIKV爆发。