Endosome positioning controls self-reactivity of nucleic acid-sensing Toll-like receptors

• Applicant: Dr. Olivia Majer
• Subject Area: Immunology ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468925051

The host immune system has the difficult task to discriminate between microbes and host-derived molecules. Certain genetic and environmental risk factors can impede this discrimination and predispose to self-reactive immune responses and disease. Recognition of nucleic acids enables the detection of diverse pathogens, including viruses and bacteria, but also exposes the host to potential self-recognition and autoimmunity. At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize host-derived RNA or DNA, respectively, and contribute to the pathology of a number of autoimmune diseases. The intracellular localization of nucleic acid-sensing TLRs to late endosomes is a key determinant in discriminating between microbial and self-derived nucleic acids. Whereas engulfed pathogens are efficiently delivered to late endosomes for their elimination, self-derived nucleic acids in the extracellular space have limited access to these compartments. Aberrant trafficking and localization of TLRs can facilitate the recognition of self-ligands and induce autoimmunity. To what extent the cellular organization and positioning of the TLR-containing endosomes themselves contribute to self-reactivity of TLRs is not known. In the proposed project we want to investigate the role of endosome positioning in nucleic acid sensing and self-recognition by TLRs. Endosomes are highly motile organelles that move between the periphery and the perinuclear region of the cell and many of their chemical properties and functions depend on their relative location. Our preliminary results show that endosome positioning has a profound impact on the response of TLRs, some of which lead to hyperactive TLR7 responses. As TLR7 hyperactivity has been associated with systemic autoimmunity in mice and humans, we propose that lysosome positioning could be an underlying risk factor for the development of autoimmune or autoinflammatory disorders. To understand how endosome positioning regulates TLR7 signaling and whether this pathway is important for maintaining immune homeostasis in vivo, we want to 1) dissect the molecular mechanism of how endosome positioning controls TLR7 responses and 2) investigate whether altered endosome positioning could lead to TLR-driven autoimmunity. Overall, this work will elucidate how cellular organization impacts immune decisions and define the molecular principles and pathways that prevent autoimmune responses to self-nucleic acids.

• DFG Programme: Research Grants