The Lieberman laboratory studies cytotoxic T lymphocytes and their role in infection and tumor immunity. They study the molecular pathways used by killer lymphocytes and their cytotoxic granule proteases, called granzymes, and pore-forming proteins, perforin and granulysin, to induce programmed cell death. They have defined a caspase-independent programmed cell death pathway activated by granzyme A. Recent work has identified an unexpected role for granzymes and granulysin in protection against bacteria and parasites. They recently uncovered the molecular basis for inflammatory cell death (pyroptosis) triggered by invasive bacteria and other danger signals and found that it is due to membrane pore formation by an inflammatory caspase-cleaved protein, gasdermin D. This mechanism also directly kills the bacteria that trigger the inflammasome. Current work focuses on innate and adaptive immune responses to invasive pathogens, including bacteria, malaria and other parasites, and fungi, including the role of decidual NK cells in protection against infection in pregnancy.
The Lieberman laboratory has been in the forefront of developing RNAi-based therapeutics and using RNAi for genome-wide screening. They were the first to demonstrate that siRNAs could protect mice from disease. They developed methods to harness RNAi to inhibit herpes and HIV transmission in animal models. They have developed strategies for cell-targeted RNAi to treat viral infection, immune disease and cancer. They are currently investigating tumor-targeted siRNAs for immunotherapy as a way to avoid autoimmune side effects of checkpoint inhibitors. They also investigate the role of endogenous microRNAs and lncRNAs in regulating cell differentiation and cancer.
- Walch M, Dotiwala F, Mulik S, Thiery J, Kirchhausen T, Clayberger C, Krensky A, Martinvalet D and Lieberman J. Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes. Cell 2014; 157:1309-1323.
- Wittrup A, Ai A, Liu X, Hamar P, Trifonova R, Charisse K, Manoharan M, Kirchhausen T and Lieberman J. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat Biotech 2015, 33: 870-878.
- Dotiwala F, Mulik S, Polidoro RB, Ansara JA, Burleigh B, Walch M, Gazzinelli RT and Lieberman J. Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites. Nature Med 2016, 22:210-216.
- Liu X, Zhang Z, Ren J, Pan Y, Magupalli VG, Wu H and Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016, 535: 153-158.
- Dotiwala F, Sen Santara S, Binker-Cosen AA, Li B, Chandrasekaran S, Lieberman J. Granzyme B Disrupts Central Metabolism and Protein Synthesis in Bacteria to Promote an Immune Cell Death Program. Cell. 2017 Nov 16;171(5):1125-1137.