Autoinflammatory diseases, such as lupus, are caused by overactivation or failure to regulate the immune system. Their origin is often poorly understood, and pathogens, environment and genetics can contribute to their onset. Type I interferonopathies are rare genetic diseases associated with an inappropriate upregulation of type I interferon (IFN) signalling. IFNs represent the first line of defence against viruses, and are induced by sensing of viral nucleic acids. Importantly, definition of the genetic basis of the type I interferonopathies has led to a coherent understanding of underlying pathology, involving previously unappreciated pathways of nucleic acid metabolism, and enabled the introduction of rational therapy targeted at blocking IFN signalling, relevant to more common autoinflammatory diseases. Thus, it is important to identify new type I interferonopathies and determine their molecular and cellular basis.
Beyond their role in energy metabolism, mitochondria are also recognised to play a role in the immune response to infection. Interestingly, both mitochondrial DNA and RNA have the potential to trigger IFN in cells. Indeed, loss of mitochondrial integrity promoting pathogenic IFN induction, through mitochondrial nucleic acids released into the cytosol, is a novel topic of high clinical and scientific interest, namely in autoinflammatory diseases. We have identified patients with mutations in a gene encoding a mitochondrial protein, ATAD3A, in which we consider the observed enhanced IFN signalling directly relevant to the associated neuropathology. Our project aims to better understand the link between mitochondrial homeostasis and IFN induction, thereby defining novel pathways relating to mitochondrial integrity, mitochondrial nucleic acids and innate immune surveillance. Specifically, we will study these relationships in the context of human disease, and we will search for further novel determinants of mitochondrial function linked to innate immune homeostasis using a unique clinical screening protocol. This will help us define new therapeutic approaches applicable to other autoinflammatory diseases.
Conclusion of the action :
We have confirmed and elucidated some aspects of the links between ATAD3A dysfunction and enhanced IFN signalling, the results of which have been published in the Journal of Experimental Medicine in 2021 and disseminated in complementary ways to the scientific community and the general public. Moreover, by identifying more mitochondrial diseases associated with upregulated IFN, we have derived new leads to further study the relationship between mitochondrial dysfunction and the IFN pathway, solidifying the basis for mitochondria-related and/or IFN-targeting therapeutic strategies. Finally, this action has allowed me to obtained a permanent research position at Inserm medical research institute in France in 2021.
