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Subversion of Innate Immunity by Ebola Virus


Ebolavirus (EBOV) is amongst the deadliest human viruses that cause hemorrhagic fever. The Zaire species (ZEBOV) is responsible for most outbreaks and highest mortality rates, with the newly identified variant, Makona (ZEBOV-Makona) responsible for the recent epidemic in West Africa. The high virulence of ZEBOV is attributed to its ability to subvert innate immune responses, notably type I interferon (IFN) production, and causes excessive inflammation. However, studies investigating how ZEBOV modulates innate immunity has mostly been extrapolated from in vitro experiments. Therefore, ZEBOV-host interactions in vivo are not fully understood. In this dissertation, I address this gap in knowledge by investigating longitudinal host responses in peripheral blood collected from cynomolgus macaques infected with ZEBOV using both immunological assays and transcriptomic analysis. We first comprehensively analyzed ZEBOV-Makona pathogenesis and discovered correlations between: increased IFNα and interferon stimulated genes (ISGs); higher inflammatory transcripts and non-classical monocytes; decreased expression of lymphocyte related genes and lymphopenia. This data also showed ZEBOV-Makona infection results in less severe and delayed appearance of clinical symptoms compared to previously identified variants. Second, transcriptomic analysis of purified immune cell subsets isolated from ZEBOV-Makona infected animals revealed that monocytes, but not T or B cells, support ZEBOV infection. Importantly, monocytes are one of the key players in mediating ZEBOV pathogenesis by initiating events that contribute to the characteristic symptoms of Ebola virus disease (EVD). Next, gene expression changes in animals infected with a recombinant ZEBOV containing mutations in VP35, which abrogate its ability to inhibit type I IFN, were indicative of a regulated innate immune response and successful development of adaptive immunity, which effectively immunized these animals against subsequent ZEBOV-Makona challenge. This data highlights the importance of type I IFN signaling and VP35 as a key virulence factor. Lastly, a promising vaccine candidate, rVSV-ZEBOV, has been shown to provide rapid protection to macaques against ZEBOV challenge. Transcriptomic analysis of animals vaccinated 7 or 3 days before challenge indicate that early expression of antiviral ISGs engendered by the vaccine can rapidly protect animals while paving the way for development of an adaptive immune response.

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