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The DAMP activity of the interferon-inducible IFI16 protein in inflammatory disease
Università degli studi di Novara
CAAD Center - Center for Translational Research on Autoimmune and Allergic Disease
Prof. Marco De Andrea / Prof. Marisa Gariglio
Prof. Marco De Andrea / Prof. Marisa Gariglio
Type of Research Project
- Basic science
What is the background of the project?
Pathogens and signals triggered by cellular perturbations engage innate immune programs. These responses use a set of germline-encoded pattern recognition receptors (PRRs) to limit the spreading of pathogens and restore tissue integrity and function. If these signals originate from the microbial world they are referred to as pathogen-associated molecular patterns (PAMPs). If the PRRs detect self-signatures, these signals are termed danger associated molecular patterns (DAMPs) or stress signals, also known as alarmins. During sepsis as well as viral infections, these PAMPs and DAMPs prime, signal, alert, and guide the immune system to fight infection. In doing that, they also mediate host cellular injury. PRRs include, among others, the interferon (IFN)-inducible protein 16 (IFI16) that is involved in sensing of cytosolic DNA. We have shown that IFI16 is aberrantly expressed in a wide range of pathological conditions, including systemic lupus erythematosus (SLE), both in the skin and the kidney of patients with lupus nephritis, inflammatory bowel disease, UV-B irradiation, viral infection (including human Cytomegalovirus, HCMV), and eventually released in the extracellular space. The extracellular IFI16 can in turn functions as a DAMP propagating ‘danger signal’ that induces a proinflammatory phenotype in neighbouring cells.
What is the aim of the project?
1. The first aim is to characterize the molecular events underlying aberrant IFI16 protein expression and release in different cellular models upon stress conditions, including HCMV infection. 2. The second aim is to use the results and to understand the mechanisms by which IFI16 can work as a DAMP, propagating danger signals per se or in cooperation with other inflammatory signals.
What techniques and methods are used?
This project relies on the use of a wide range of cellular and molecular biology techniques. Both primary and continuous cell lines are employed as models to investigate their response to inflammatory stimuli. Gene expression by quantitative PCR (Polymerase Chain Reaction) and cytokine release by ELISA (enzyme-linked immunosorbent assay) are employed as readout of treatment; Western blotting, flow cytometry, immunohistochemistry and immunofluo-rescence to evaluate the expression and localization of cellular and viral markers. Moreover, the CAAD (Center on Autoimmune and Allergic Diseases) lines up a gold standard equipment for innovative research, including a surface plasmon resonance platform (SPR, BiacoreX100) to characterize the interaction of small molecules, as well as genomic and proteomic facilities.
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
After the training period, the student should be able to demonstrate knowledge of the main cellular and molecular biology techniques approached. Moreover, he/she should demonstrate to be able dealing with the different theoretical aspects related to cell response to the pathogen-associated molecular patterns (PAMPs) and danger associated molecular patterns (DAMPs). In particular, they will learn how a cellular protein involved in antiviral response (the interferon (IFN)-inducible protein 16 - IFI16), can also behave as a DAMP propagating ‘danger signal’ and inducing a proinflammatory phenotype in neighbouring cells.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Preliminary readings will be provided, focused on the specific topic. The student will be involved in lectures and seminars provided by collaborators or by external speakers.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a scientific report - The student will prepare an abstract
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Knowledge of biology and biochemistry. Subjects passed: histology, biochemistry, biology
Are there any legal limitations in the student’s involvement
Please don’t share the results of the study
Type of students accepted
This project accepts: - Medical students
- 1: Caneparo V; Landolfo S; Gariglio M; De Andrea M. The Absent in Melanoma 2-Like Receptor IFN-Inducible Protein 16 as an Inflammasome Regulator in Systemic Lupus Erythematosus: The Dark Side of Sensing Microbes. Front Immunol. 2018 May 28;9:1180. doi: 10.3389/fimmu.2018.01180. eCollection 2018.
- 2: Caneparo V; Pastorelli L; Pisani LF; Bruni B; Prodam F; Boldorini R; Roggenbuck D; Vecchi M; Landolfo S; Gariglio M; De Andrea M. Distinct Anti-IFI16 and Anti-GP2 Antibodies in Inflammatory Bowel Disease and Their Variation with Infliximab Therapy. Inflamm Bowel Dis. 2016 Dec;22(12):2977-2987.
- 3: Biolatti M; Dell'Oste V; Pautasso S; von Einem J; Marschall M; Plachter B; Gariglio M; De Andrea M; Landolfo S. Regulatory Interaction between the Cellular Restriction Factor IFI16 and Viral pp65 (pUL83) Modulates Viral Gene Expression and IFI16 Protein Stability. J Virol. 2016 Aug 26;90(18):8238-50. doi 10.1128/JVI.00923-16.
- 4: Lo Cigno I; De Andrea M; Borgogna C; Albertini S; Landini MM; Peretti A; Johnson KE; Chandran B; Landolfo S; Gariglio M. The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters. J Virol. 2015 Aug;89(15):7506-20. doi: 10.1128/JVI.00013-15.
- 5: Bawadekar M; De Andrea M; Lo Cigno I; Baldanzi G; Caneparo V; Graziani A; Landolfo S; Gariglio M. The Extracellular IFI16 Protein Propagates Inflammation in Endothelial Cells Via p38 MAPK and NF-κB p65 Activation. J Interferon Cytokine Res. 2015 Jun;35(6):441-53. doi: 10.1089/jir.2014.0168.
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