Innate immunity plays a critical role in initiating immune response and pathogen clearance upon microbial infection. Using pattern recognition receptors, including intracellular receptors or cell surface receptors, immune cells sense and respond to pathogenic microbial infection. This triggers activation of various anti-pathogen signaling cascades leading to anti-microbial, type I interferon (IFN), and/or proinflammatory cytokine responses. Understanding the effect of various microbial infections on receptors and signaling pathways will provide molecular insights into the host defense machinery and potential therapeutic targets for treating microbial infection. In contrast, uncontrolled nucleic acid sensing, especially self-nucleic acid sensing, and excessive production of type 1 IFN and proinflammatory cytokines, have been implicated in the development of autoimmune diseases such as systemic lupus erythematosus (SLE). Knowing the self-nucleic acid sensing systems in immune cells will help us develop receptor antagonists as a new form of therapy for autoimmune diseases.
Studies conducted by Dr. Zhang ’s group indicate that many helicases are critical cytosolic sensors that recognize RNA, DNA, or c-di-GMP, triggering the IFN host immune response mediated by MAVS, TRIF, or STING. The anti-microbial pathogen activities of these helicases are regulated by protein ubiquitination. Further studies indicate that these helicases as well as the well-known IFI16, play little role in sensing neutrophil-derived mitochondrial DNA (mtDNA), which is the major inducer of IFN in SLE. Dr.
Zhang ’s group has:
i) Characterized DNA-binding proteins in monocyte. They expect to identify the cytosolic sensor to mtDNA.
ii) Screened all 70 members in the TRIM family and has found that at least 6 other TRIMs play important roles in regulating nucleic acid sensing.
Together, their studies will focus on revealing the unknown host defense mechanisms, autoimmune mechanisms, and ubiquitin-signaling pathways.
