Ebola virus infection of the female reproductive system

摘要/摘要 埃博拉病毒(丝状病毒科)是引起埃博拉病毒病(EVD)的病原体，其特征是 人类中的出血热，达到高死亡率(≥40%)。埃博拉病毒的性传播 在2014-2016年西非大规模疫情期间，首次记录了男性对女性的幸存者。然后就是这个 据报道，感染途径可能是2015至2015年间多起EBOV疫情爆发的原因 2016年。幸存者的精液传染性后来被记录下来，至少在发病后179天。 同一暴发期间性行为在病毒传播中的作用的数学模型 这表明，禁欲加上传染性患者的隔离，可以阻止疫情的爆发。截至2020年6月2日， 刚果民主共和国持续爆发的EBOV疫情描述了3463例，2280人死亡，以及 目前还没有数据表明哪种感染途径是传播的主要原因，以及 提高幸存者的情境意识，以传播埃博拉病毒。最近，我们小组证明了人类的阴道 上皮细胞容易感染埃博拉病毒，支持高效的病毒复制，导致 强烈的促炎反应。此外，我们还评估了阴道聚苯醚的抗病毒效果。 作为对策的羧甲基(PPCM)杀菌剂可显示出抑制病毒复制的作用 以及病毒在这些细胞中诱导的炎症反应。总而言之，这些事实支持了迫切需要 为这种感染途径和预防病毒传播的治疗方法开发新的实验模型 无保护措施的性交。 我们的长期目标是更好地了解埃博拉病毒的性传播，并确定预防措施 避孕套以外的其他方法。这项建议的目的是研究埃博拉病毒在女性中的发病机制。 在使用相关的人类女性生殖系统体外模型进行性传播之后 作为一种易感的小鼠模型。我们的中心假设是人类女性生殖系统 易感染埃博拉病毒导致不典型的埃博拉病毒临床表现和实验室检查 与使用其他更有记录的途径感染埃博拉病毒后观察到的特征进行比较 感染的可能性。为了验证我们的驾驶假说，我们提出了以下具体目标：(1)表征 用体外培养的人阴道上皮细胞模型研究埃博拉病毒感染和炎症 在气液界面，(2)建立经阴道感染埃博拉病毒病(EVD)的体内模型 (3)评价PPCM的体内外保护抗病毒作用。这个 拟议的研究将为研究丝状病毒的致病性开发新的模型，并进一步发展PPCM AS 一种治疗埃博拉病毒感染的杀微生物剂。

SUMMARY/ABSTRACT Ebola virus (family Filoviridae) is the causative agent of Ebola virus disease (EVD), which is characterized by hemorrhagic fever in humans, reaching high mortality rates (≥40%). Sexual transmission of Ebola virus from a male survivor to a woman was first documented during the large 2014-2016 West African outbreak. Then this route of infection was reported to be likely responsible for multiple EBOV outbreak flare-ups between 2015 and 2016. Infectivity of the semen of survivors was later documented for at least 179 days after the onset of disease. Mathematical modelling of the contribution of sexual behavior in virus transmission during that same outbreak showed that abstinence, along with infectious patient isolation, could stop an outbreak. As of June 2nd, 2020, the on-going EBOV outbreak in the Democratic Republic of the Congo describes 3463 cases with 2280 deaths, and there are no data available as to which route of infection is primarily responsible of transmission and the situational awareness of survivors to spread EVD. Recently, our group demonstrated that human vaginal epithelial cells are susceptible to infection with Ebola virus, support productive viral replication resulting in a robust proinflammatory response. Furthermore, we evaluated the antiviral efficacy of the vaginal Polyphenylene Carboxymethylene (PPCM) microbicide as a countermeasure and could show suppression of virus replication and virus-induced inflammatory response in these cells. Altogether, these facts support the critical need to develop new experimental models for this route of infection and therapeutics preventing virus transmission during unprotected sexual intercourse. Our long-term goal is to better understand sexual transmission of Ebola virus, and to identify prophylactic methods other than condoms. The objective in this proposal is to investigate Ebola virus pathogenesis in women following sexual transmission using a relevant in-vitro model of the human female reproductive system as well as a susceptible mouse model. Our central hypothesis is that the human female reproductive system is susceptible to Ebola virus infection leading to atypical clinical manifestations of EVD and laboratory characteristics compared to those observed after infection by Ebola virus using other more documented routes of infection. To interrogate our driving hypothesis, we propose the following Specific Aims: (1) Characterize Ebola virus infection and inflammation in-vitro using a model of the human vaginal epithelium cultured at air-liquid interface, (2) Establish an in-vivo model of Ebola Virus Disease (EVD) following intravaginal virus challenge, and (3) Evaluate the protective antiviral efficacy of PPCM in-vitro and in-vivo. The proposed studies will develop novel models for research of filovirus pathogenicity and further develop PPCM as a microbicide for Ebola virus infection.