During this project we have been able to uncover novel determinants of innate immunity and nucleic acid sensing in human cells, including hematopoietic stem cells.
Our studies of antiviral activity in the context of HSC gene therapy have revealed previously unknown molecular determinants involved in antiviral control by innate immune factors. These studies together with the historical times of the COVID-19 pandemic, have also allowed us to explore the role of these factors also in the context of the pandemic causing SARS-CoV2 infection. Together, these studies provide significant insight into how these antiviral factors impact gene therapy and viral pathogenesis, paving the way for the development of novel strategies to either overcome or enhance this restriction as needed.
In association with the studies on these antiviral mechanisms of actions we are understanding how we can counteract these antiviral factors in the context of enhanced gene therapies. These studies inform the development of novel, easier to produce, enhancers of gene therapy and provide insight into how antiviral responses are regulated in human stem cells. In addition, our studies on pharmacological enhancement of gene therapy in HSC is uncovering additional effects our compound seems to have on pathways relevant for stem cell biology. We predict these findings may have particular relevance in the context of diseased HSC that could benefit from the transduction enhancer not only for enhanced gene transfer but also in terms of fitness. Similarly, other blood cell types that are attractive targets for advanced immunotherapies such as CAR-T cells will potentially benefit from the use of such enhancers as their genetic manipulation remains challenging and prolonged ex vivo culture leads to exhaustion.
Importantly, we have discovered a novel, still cryptic, innate sensor of retroviruses that detects incoming viral particles in HSC and primary macrophages, leading to robust activation of type I IFN responses. Much of the focus in the field of innate immunity against viral infections has been directed towards sensing of nucleic acids such as RNA and DNA upon viral infections. Structural recognition of incoming virions has been shown to occur for HIV but very little knowledge on potential recognition of other retroviral particles is available. Identifying novel host factors of the innate sensing machinery wired towards structural components of viral pathogens can have potentially broad acting implications for the development not only of enhanced gene and antiviral therapies but also to harness these responses immunostimulatory applications in the context of antitumoral approaches.
Our work has also enabled us to contribute to the understanding of how these innate immune sensing pathways can contribute to other autoimmune pathologies beyond the monogenic blood disorders that can be treated with gene therapies.
