Development of Interfering Strategies Against the Innate Immune Inhibition by the VP35 Ebola virus Protein, a Key Viral Target

Relevant health-threatening pathogens developed during their evolution a number of strategies for counteracting the defense schemes of the host organisms and escape immune response. Recent outbreaks over the last 10 years of Ebola, West Nile, Chikungunya, Zika, Middle Eastern Respiratory and other emerging/re-emerging RNA viruses continue to teach a lesson to humankind and scientific community: we still need to further understand the virus–host interactions that regulate disease severity and infection outcome, in order to develop efficient strategies to counteract their anti-immunogenic activity. As part of the early host antiviral defense, the innate immune system mediates pathogen recognition setting up potent antiviral programs that aid to limit virus replication, virus spread, and activate adaptive immune responses. On the other side of the barricade, even viral pathogens evolved several strategies to counteract pathogen recognition and cell-intrinsic antiviral responses, dramatically orchestrating a profound reorganization of the host cell metabolism to create a favorable environment for viral multiplication. Ebola virus (EBOV), one of the most virulent and deadly pathogen ever known and faced by humankind, etiological agent of hemorrhagic fevers in humans and non-human primates today called Ebola virus disease (EVD), can be undoubtedly considered the perfect example of a potent host organism immune response inhibitor. Thanks to the action, among all the virus-coded proteins, of the viral protein 35 (VP35), EBOV determines a very opportune damage to the innate immune responses, a fundamental step to ensure the maximum efficiency in case of EBOV infection, contributing to disease progression and severity. Therefore, the PhD thesis here presented will focus on the study of different approaches that can be adopted to improve the host innate immune response when inhibited by the presence of the viral protein VP35 and on the development of efficient strategies for subverting this inhibitory blockade, with particular interest to: i. searching for molecules, synthetic as well as of natural origin, capable to stimulate the innate immune response of the host organism as well as to counteract the inhibition of the immune response mediated by EBOV VP35; ii) searching for molecules, synthetic as well as of natural origin, capable to directly interfere with a specific domain of the EBOV VP35 protein and inhibiting its biological anti-immunity function; iii) developing an antibody-based approach to directly inhibit the anti-immunity activity of the VP35 protein.