Sad, Subash - University of Ottawa - Department of Biochemistry, Microbiology and Immunology

个人简介

B.Sc. (Specialisation: Mathematics), University of Kashmir (1983) M.Sc (Biochemistry), University of Kashmir (1986) Ph.D. (Immunology) 1992, Natlonal lnstitute of Immunology, New Delhi

研究领域

Inflammation touches every aspect of health and disease throughout our lives. Our laboratory studies the mechanisms that maintain a healthy immune system and prevent the development of inflammatory diseases. In particular, we are interested in the intricate mechanisms that control cell death in immune cells. While under normal conditions, immune cells are essential to provide protection against the continuous challenge of pathogens in our environment, an imbalance in the death of immune cells can result in chronic inflammation, collateral damage to the surrounding tissue and throughout the body. In particular, we are studying cell death within macrophages. Macrophages are important cells of the innate immune system that engulf pathogens and release powerful immune signals that can have both inflammatory and anti-inflammatory effects. We have identified novel mechanisms that control a newly discovered form of programmed necrotic cell death, known as necroptosis. When macrophages die by necroptosis their cell membrane ruptures, spilling the cell contents out into the body and leading to massive inflammation. We have identified that the production of a key inflammatiory signal (interferon) is an essential upstream inducer of this inflammatory cell death. By improving the understanding of the mechanisms of necroptosis this research will lead to the development of new therapeutic approaches to treat chronic inflammatory diseases. We are also evaluating the mechanisms that lead to the generation and maintenance of T cell memory. CD8 T cells have the unique ability to specifically and rapidly kill cells that are infected with pathogens. By targeting infected cells, CD8 T cells can prevent the spread of pathogens and eliminate them from the body. Development of means to activate such cells is therefore highly sought after for vaccine approaches as efficacy of vaccines often depends on the generation and maintenance of pathogen or tumor-specific cytolytic memory CD8 T cells. We aim to better understand the mechanisms of T cell activation as well as the processes of cell death, which remove activated T cells through a process known as contraction. Ultimately we hope to understand how to generate long-lived memory CD8 T cells which can eliminate chronic pathogens from the body.

近期论文

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McComb S., Cessford E., Alturki N.A., Joseph J., Shutinoski B., Startek J.B., Gamero A.M., Mossman K. and Sad S. (2014). Type I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in Macrophages. Proc. Natl. Acad. Sci. USA (PNAS). Aug 5;111(31):E3206-13. doi: 10.1073/pnas.1407068111. Epub 2014 Jul 21. McComb S., Shutinoski B., Thurston S., Cessford E., Kumar K. and Sad S. (2014). Cathepsins limit macrophage necroptosis through cleavage of Rip1 kinase. J. Immunol. Jun 15;192(12):5671-8. Tai L.H., Zhang J., Scott K.J., de Souza C.T., Alkayyal A.A., Ananth A.A., Sahi S., Adair R.A., Mahmoud A.B., Sad S., Bell J.C., Makrigiannis A.P., Melcher A.A., Auer R.C. (2013). Perioperative influenza vaccination reduces postoperative metastatic disease by reversing surgery-induced dysfunction in natural killer cells. Clin. Cancer Res. Sep 15;19(18):5104-15. Nguyen T, Robinson N., Allison S.E., Coombes B.K., Sad S., Krishnan L. (2013). IL-10 produced by trophoblast cells inhibits phagosome maturation leading to profound intracellular proliferation of Salmonella enterica Typhimurium. Placenta. 2013 Sep;34(9):765-74. Tzelepis F., Joseph, J., Haddad H.K., MacLean S., Dudani R., Agenes F., Peng S.L., Sekaly R-P., Sad S. Intrinsic role of FoxO3a in the development of CD8+ T cell memory. J. Immunol. 2013 February 1, 190( 3): 1066-1075. Tzelepis F., Alcon V., Young K.G., Gurnani K., Everson E.S., Rüssmann H., Krishnan L. and Sad S. (2012). Forcing recognition of infected targets by CD8+ T cells can override immune-evasion and convert a chronic into an acute infection: The impact of antigenic location. Cell Reports: Dec 27;2(6):1710-21. Hussack G., Keklikian A., Alsughavvir J., Hanifi-Moghaddam P., Arbabi-Ghahroudi, M., Van Faassen H., Hou ST, Sad S., MacKenzie R. and Tanha J. (2012). A VL single-domain antibody library shows a high-propensity to yield non-aggregating binders. Protein Engineering, Design and Selection, 25(6); 313-318. McComb S, Cheung HH, Korneluk RG, Wang W., Krishnan L. and Sad S. (2012) cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation. Cell death and differentiation, Nov;19(11):1791-1801. Robinson N., McComb S., Mulligan R., Dudani R., Krishnan L. and Sad S., (2012) Type I interferon induces necroptosis in macrophages during Salmonella Typhimurium infection. Nature Immunol., Oct;13(10):954-962. Stark FC, Gurnani K, Sad S, Krishnan L (2012). Lack of functional selectin ligand interactions compromises long term tumor protection by CD8 T cells. PLoS One. Feb; 7(2): e32211. Young K.G., MacLean S., Dudani R., Krishnan L., and Sad S. (2011). CD8+ T cell primed in the periphery provide time-bound immune surveillance to the central nervous system. J. Immunol. Aug 1;187(3):1192-200. McComb S, Mulligan R, Sad S. (2010). Caspase-3 Is Transiently Activated without Cell Death during Early Antigen Driven Expansion of CD8 T Cells In Vivo. PLoS One. Dec; 5(12): e15328. Chattopadhyay A., Robinson N., Sandhu JK., Finlay BB., Sad S., Krishnan L. (2010). Salmonella Typhimurium induced placental inflammation and not bacterial burden correlates with pathology and fatal meternal disease. Infect. Immun., May; 75(5): 2292-301. Krishnan L., Pejcic-Karapetrovic B., Gurnani K., Zafer A. and Sad S. (2010). Pregnancy does not deter the development of a potent maternal protective CD8+ T cell acquired immune response against Listeria monocytogenes despite preferential placental colonization. Am. J. Reprod. Immunol. Jan; 63(1):54-65. Russell MS., Dudani R., Krishnan L. and Sad S. (2009). IFN-g expressed by T cells regulates the persistence of antigen-presentation by limiting the survival of dendritic cells. J. Immunol. Dec. 15; 183(12): 7710-8. Wong CE, Sad S. and Coombes BK. (2009). Salmonella exploits Toll-like receptor signaling during the host-pathogen interaction. Infect. Immun. Nov;77(11):4750-60. Albaghdadi H., Robinson N., Finlay B., Krishnan L and Sad S. (2009). Selectively reduced intracellular proliferation of Salmonella enterica serovar Typhimurium within APCs limits antigen presentation and development of a rapid CD8 T cell response. J. Immunol. Sep 15;183(6):3778-87. Stark F., Sad S., Krishnan L. (2009). Intracellular bacteiral vectors that induce CD8+ T cells with similar cytolytic abilities but disparate memory phenotypes provide contrasting tumor protection. Cancer Research. May 12; 69(10): 4327-34.