| Project Detail |
Cellular recognition of ‘non-self’ viral nucleic acids activates a powerful interferon-mediated defence that is tightly regulated to prevent aberrant immunopathology in the absence of infection. Thus, it is widely believed that immunostimulatory ‘self’ nucleic acids must be strictly silenced by the cell, particularly viral-mimetic endogenous retroelement nucleic acids. Indeed, disruption of retroelement repression is linked to some autoimmune diseases, but therapies are limited by lack of knowledge on how this may be governed.We recently discovered that the respiratory RNA virus, influenza virus, triggers a novel host defence mechanism in infected cells via SUMO-dependent loss of TRIM28-mediated endogenous retroelement silencing. This leads to expression of antiviral immune effectors through ‘self’ immunostimulatory viral-mimetic nucleic acids and/or cis-acting gene-regulatory mechanisms. This implies, unexpectedly, that the TRIM28-based machinery normally responsible for silencing dangerous endogenous ‘self’ elements has a key role in determining anti-pathogen defence. Consequently, cells must have hitherto unappreciated physiological instruments to reversibly silence immunoregulatory endogenous retroelements via TRIM28. Understanding the mechanisms underlying switchable control of this system in response to infection will be critical to develop a framework exploiting this concept for future anti-viral or anti-autoimmune strategies.In this project, we will combine state-of-the art molecular virology with cutting-edge in situ quantitative proteomic methodologies to define and mechanistically dissect the influenza virus activated host cell pathways that trigger infection-induced changes to TRIM28 post-translational modifications, TRIM28 function, and the subsequent antiviral immune response. We will also employ advanced nucleic acid sequencing technologies to survey the spectrum and specificity of infection-induced endogenous retroelements with the future aim of manipulating levels of selected infection-induced retroelements and subsequently assessing their contributions to antiviral immunity. An important aspect of the project will be to cross-validate findings in primary human airway epithelial cell cultures where possible, and to compare newly-identified mechanisms across different immune cell-types, which will assess their universality or cell specificity in physiologically-relevant tissues.Our fundamental studies should illuminate the molecular details underpinning a non-canonical antiviral defence response based on host control of ‘self’ immunoregulatory endogenous retroelements. Cues learned from newly-discovered cellular regulators could suggest novel avenues for the rational design of tunable therapeutic strategies to either boost or dampen this form of immunity in order to mitigate pathogenic infections or some autoimmune disorders.
Grant number
214957
Funding scheme
Project funding
Call
Projects Life Sciences 2022 October
Approved amount
850,000 CHF
Status
Ongoing |
