Project description
DNA: common culprit of ageing and immunity?
Inflammation is our immune system’s response to harmful stimuli such as pathogens or injury. One of the key mediators of inflammation is DNA, which triggers the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway of innate immunity. The EU-funded ImAgine project is interested to understand the mechanisms by which cells detect and react to DNA, inducing inflammatory processes. Researchers aim to identify key players in the process and develop novel anti-inflammatory medicines. They are working under the hypothesis that inflammation constitutes one of the hallmarks of ageing and age-related disorders, which could be treated by targeting the inflammatory process.
Objective
The innate immune system has evolved signalling receptors, which detect various stresses including microbial infection but also signals emanating from non-infectious cellular damage. Upon activation, these signalling receptors can trigger a variety of distinct effector responses collectively aimed towards maintaining the integrity of the host. The recognition of cytosolic DNA through the cGAS-STING pathway is a fundamental mechanism through which pathogens and cellular stress evoke an inflammatory response. Recently, we discovered a new role of the cGAS-STING pathway in promoting cellular senescence, a critical stress response program that is emerging as a key driver of aging. On the basis of this finding, the overarching gaol of ImAgine is to further explore the molecular links that exist between the mechanisms of innate immune signalling and those underlying aging processes. Specifically, we will address whether the cGAS-STING pathway acts as a contributor to age-associated phenotypes and we will interrogate mitotic perturbations as a physiological source of age-associated damage that activates the innate DNA sensing machinery. Another intriguing possibility emerging from our work is that cellular senescence is relevant for the host response against pathogens. Utilising an array of genetic and pharmacological tools, we will challenge this idea and molecularly decipher the role of senescent cells in physiological models of acute and chronic infection. A detailed picture of the interplay between innate immune pathways and cellular ageing will not only be a critical step towards a global understanding of fundamental host response mechanisms, but may also provide new concepts for the treatment of diseases that are associated with infectious diseases or ageing.
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Funding Scheme
ERC-STG - Starting GrantHost institution
1015 Lausanne
Switzerland