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Project 31
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Project 31

Nirmal Robinson

The role of SIRT1 in cell autonomous defence against intracellular pathogens

Institute for Medical Microbiology, Immunology and Hygiene, Universitiy Hospital of Cologne

Summary
Macrophages are pivotal in the innate immune defense against pathogens and in maintaining tissue homeostasis. Our previous studies have shown that macrophage-mediated bacterial killing and antigen presentation are critical for the control of Salmonella enterica serovar Typhimurium (S. typhimurium).

Our more recent findings reveal that the pathogen escapes macrophage defense by inducing a proinflammatory, necroptotic cell death. This form of cell death is caused by mitochondrial damage and ATP depletion, leading to adenosine monophosphate kinase (AMPK) activation.

Sirtuin1 (Sirt1) is a lysine deacetylase, which cooperates with AMPK in inducing mitochondrial biogenesis, thus maintains energy homeostasis in a cell. Our studies also revealed that SIRT1 is downregulated in macrophages upon infection with S. typhimurium.

However, the causes and consequences of pathogen-mediated downregulation of Sirt1 are less understood. This project is aimed to reveal the role of SIRT1 in cell-autonomous defense against S. Typhimurium.

Our ongoing study revealed that Sirt1 is translocated to phagosomes by default. We hypothesize that Sirt1 could regulate the link between the energy-consuming process of phagosomal maturation and energy-generating mitochondrial metabolism.

Our key objective of the funding period is to study the functional role of Sirt1 in phagosome biogenesis and processing of intracellular pathogens. It has been previously reported that Sirt1 regulates autophagy by deacetylating both Atg5 and Atg7. Autophagy is critical for the clearance of S. typhimurium by host cells.

We have observed that overexpression of Sirt1 in macrophages infected with S. typhimurium enhances the maturation of autophagosomes to autophagolysosme. Therefore, we propose to study the role of Sirt1 in pathogen-specific autophagy.

Finally, the in vivo significance of Sirt1 in innate immune defense against intracellular bacterial pathogens will be studied using mice conditionally knocked down for Sirt1 in myeloid cells. Taken together, this project aims to decipher the function of Sirt1 in cell autonomous defense against pathogens.

List of publications

Persa OD, Jazmati N, Robinson N, Wolke M, Kremer K, Schweer K, Plum G, Schlaak M. (2014) A pregnant woman with chronic meningococcaemia from Neisseria meningitidis with lpxL1-mutations. Lancet. 384(9957): 1900.

Nguyen T, Robinson N, Allison SE, Coombes BK, Sad S and Krishnan L. (2013) IL-10 produced by trophoblast cells inhibits phagosome maturation leading to profound intracellular proliferation of Salmonella enterica Typhimurium. Placenta 34(9):765-774.

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 Immunology 13(10):954-962.

Rybniker J, Nowag A, van Gumpel E, Nissen N, Robinson N, Plum G and Hartmann P. (2010) Insights into the function of the WhiB-like protein of mycobacteriophage TM4 – a transcriptional inhibitor of WhiB2. Molecular Microbiology. 77(3): 642-57.

Chattopadhyay A, Robinson N, Sandhu JK, Finlay BB, Sad S and Krishnan L. (2010) Salmonella Typhimurium induced placental inflammation and not bacterial burden correlates with pathology and fatal maternal disease. Infection and Immunity 78(5):2292-301.

Albaghdadi H, Robinson N, Dudani R, Krishnan L and Sad S. (2009) Selectively reduced intracellular proliferation of Salmonella Typhimurium within antigen-presenting cells limits antigen-presentation and development of a rapid CD8 T cell response. Journal of Immunology 183(6):3778-87.

Robinson N, Kolter T, Rybniker J, Wolke M, Hartmann P, Plum G. (2008) A Mycobacterial glycolipid inhibits phagosome maturation and subverts proinflammatory cytokines. Traffic 9(11):1936-47

Rybniker J, Plum G, Robinson N, Small PL and Hartmann P. (2008) Identification of three cytotoxic early proteins of mycobacteriophage L5 leading to growth inhibition in Mycobacterium smegmatis. Microbiology. 154 (Pt 8): 2304-14.

Robinson N, Wolke M, Ernestus K, Plum G. (2007) A mycobacterial gene involved in synthesis of an outer cell envelope lipid is a key factor in prevention of phagosome maturation. Infection and Immunity 75(2): 581-591.

Stephen TL,  Fabri M, Groneck L, Röhn TA, Hafke H, Robinson N, Rietdorf J, Schrama D, Becker JC, Plum G, Krönke M, Kropshofer H, and Kalka-Moll WM. (2007) Transport of Streptococcus pneumoniae Capsular Polysaccharide in MHC Class II Tubules. PLoS Pathogens. 16;3(3):e32.

Reviews

Fischer J, Jung N, Robinson N, Lehmann C. (2015) Sex differences in immune responses to infectious diseases. Infection. 43(4): 399-403