Thursday, November 21, 2024
11/21/2024
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.
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