PYRAMID · PYHIN-Regulated Memory T cell protection for Infectious Diseases

Pyrin and HIN domain (PYHIN) proteins play an integral role in the innate immune response to DNA and RNA viruses via direct detection of viral DNA and transcriptional regulation of pro-inflammatory and anti-viral cytokines respectively. Although expressed by various cells of the myeloid lineage, including some classical antigen presenting cells, the role of PYHINs in the context of T cell-mediated adaptive immunity has yet to be investigated. This project aims to elucidate how PYHIN proteins modulate acute and long-term CD8+ memory T cell responses to influenza A virus (IAV), a respiratory RNA virus which causes significant morbidity and mortality annually. Current seasonal IAV vaccines, exhibit variable efficacy and the neutralising antibodies they induce cannot protect against alternative IAV strains, particularly those with pandemic potential. In contrast, IAV-specific CD8+ memory T cells can elicit such cross-protective immunity by targeting conserved viral proteins, thus making the identification of mechanisms which give rise to these cells high priority in the search for a universal IAV vaccine. Herein, we will perform in-depth characterisation of PYHIN expression in human and murine dendritic cells. We will also perform genetic manipulation of PYHIN expression in primary immune cells to interrogate functionality and undertake infection studies in transgenic mice lacking certain PYHIN family members to determine their role in the formation of IAV-specific T cell memory in vivo. Overall, this project is extremely timely, providing crucial mechanistic insight which can inform rational vaccine design aimed at eliciting cross-protective T cell responses to respiratory RNA viruses.