Prof. Mordechay[Motti] Gerlic

Associate Prof. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine

2002-2006            Kreitman PhD Fellow - Predoctoral trainee in microbiology and immunology, Ben-gurion university, Israel

2008-2011            CCFA Fellow - Postdoctoral trainee in cell death, inflammation.

2011-2014            Senior Research Officer, Inflammation Division, Walter and Eliza Hall Institute of Medical Research, 3052, VIC, Australia.

2011-2014            Honorary appointment, Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.

2014-pres             Senior lecturer (Lab head), Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University.

Cell Death and Immune Response: the Role of Necroptosis and Pyroptosis in Inflammation

Cell death is an essential cellular process during development, but also facilitates the removal of damaged or infected cells, and is required for the resolution of innate and adaptive immune responses.

Our research focus is the understanding of the inflammatory response, with particular emphasis on novel NLRs (Nucleotide-binding domain and Leucine-rich repeat containing Receptors), and the non-apoptotic forms of cell death during infection. In particular we are interested in how pathogens (viruses and bacteria) are recognized by the innate immune system to facilitate these signals and how some pathogens evolve to target these mechanisms and prevent the host inflammatory response.

Recently, we discovered a physiological role for NLRP1 in driving a lethal, systemic inflammatory disease that is triggered by Caspase-1 activation and IL-1β production. Remarkably, active NLRP1 triggered a Caspase-1-dependent form of cell death, known as pyroptosis. This cell death affected hematopoietic stem and progenitor cells (HSPC), resulting in leukopenia at steady state, and cytopenia, bone marrow hypoplasia and immunosuppression, during periods of hematopoietic stress induced by chemotherapy or viral infection. Our recent research into how pathogens modulate complexes such as the NLRP1 inflammasome has defined mechanism by which Vaccinia Virus protein, F1L, target inflammasomes directly by binding and inhibiting the NLRP1 inflammasome formation. These findings reveal novel mechanism for viruses to evade host innate immune responses. Furthermore, we recently changed the thinking of necroptosis, which was thought to be RIPK1-dependent. We found the opposite, namely, that RIPK1 acts as a negative regulator of necroptosis, and loss of RIPK1 results in a lethal multi-organ systemic inflammatory response.

Complete list of published work at My Bibliography:  http://www.ncbi.nlm.nih.gov/pubmed/?term=Gerlic+M

Murphy AJ, Kraakman MJ, Kammoun HL, Dragoljevic D, Lee MK, Lawlor KE, Wentworth JM, Vasanthakumar A, Gerlic M, Whitehead LW, DiRago L, Cengia L, Lane RM, Metcalf D, Vince JE, Harrison LC, Kallies A, Kile BT, Croker BA, Febbraio MA, Masters SL. IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome. Cell Metab, January 2016. PMID: 26603191

Uboldi AD, McCoy JM, Blume M, Gerlic M, Ferguson DJ, Dagley LF, Beahan CT, Stapleton DI, Gooley PR, Bacic A, Masters SL, Webb AI, McConville MJ, Tonkin CJ. Regulation of Starch Stores by a Ca(2+)-Dependent Protein Kinase Is Essential for Viable Cyst Development in Toxoplasma gondii. Cell Host Microbe. December 2015. PMID: 26651943

Blume M, Nitzsche R, Sternberg U, Gerlic M, Masters SL, Gupta N, McConville MJ. The gluconeogenic enzyme fructose bisphosphatase regulates glucose catabolism in Toxoplasma gondii and is essential for replication and virulence, CELL-HOST-MICROBE-D-14-00707R2, Cell host & Microbe, August 2015. PMID: 26269956

Lawlor KE, Khan N, Mildenhall A, Gerlic M, Croker BA, D’Cruz AA, Hall C, Spall SK, Anderton H, Masters SL, Rashidi M, Wicks IP, Alexander WS, Mitsuuchi Y, Benetatos CA, Condon SM, Wong WWL, Silke J, Vaux DL, Vince JE. RIPK3 promotes cell death, NLRP3 inflammasome and interleukin-1 activation in the absence of MLKL, Nature Communication, February 2015. PMID: 25693118

O’Donnell JA, Kennedy CL, Pellegrini M, Nowell CJ, Cengia L, Masters SL, Hartland EL, Roberts AW, Gerlic M, Croker BA. Fas controls neutrophil lifespan during viral and bacterial infection. Journal of Leukocyte Biology, December 2014. PMID: 25473101

Rickard JA*, O’Donnell JA*, Evans JM*, Lalaoui N, Poh AR, Rogers T, Vince JE, Lawlor KE, Ninnis RL, Anderton H, Hall C, Spall SK, Phesse TJ, Abud HE, Cengia LH, Corbin J, Mifsud S, Di Rago L, Metcalf D, Ernst M, Dewson G, Roberts AW, Alexander WS, Murphy JM, Ekert PG, Masters SL, Vaux DL, Croker BA*, Gerlic M*#, Silke J*#. RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis. Cell, 157 (5), 1175-1188, May 22, 2014 *These authors contributed equally to this work. # Corresponding authors. PMID: 24813849

Correa RG, Krajewska M, Ware CF, Gerlic M, Reed JC. The novel NLR-related protein NWD1 is associated with prostate cancer progression and impacts androgen receptor signalling. Oncotarget. March 26, 2014. PMID: 24681825

Gerlic M, Croker BA, Cengia LH, Moayeri M, Kile BT, Masters SL. NLRP1a expression in Srebp1a deficient mice. Cell Metabolism, March 4, 2014. PMID: 24606891

Gerlic M*, Faustin B*, Postigo A, Yu ECW, Gombosuren N, Krajewska M, Flynn R, Croft M, Way M, Satterthwait A, Liddington RC, Salek-Ardakani S, and Reed JC. Vaccinia Virus F1L protein promotes virulence by inhibiting NLR inflammasome activation. PNAS, April 19, 2013 doi: 10.1073/pnas.1215995110. *These authors contributed equally to this work. PMID: 23603272

Proell M, Gerlic M, Mace PD, Reed JC, Riedl SJ. The CARD plays a critical role in ASC foci formation: New insights into inflammasome signaling. Biochem Journal, PMID 23110696, 2012 October. PMID: 23110696

Masters SL*, Gerlic M*, Metcalf M, Preston S, Pellegrini M, O’Donnell JA, McArthur K, Baldwin TM, Chevrier S, Nowell CJ, Cengia LH, Henley KJ, Collinge JE, Kastner DL, Feigenbaum L, Hilton DJ, Alexander WS, Kile BT*, Croker BA*. NLRP1 inflammasome induces pyroptosis of hematopoietic progenitor cells. Immunity, Volume 37, Issue 6, 1009-1023, 14 December 2012. *These authors contributed equally to this work. PMID: 23219391

Haneklaus M, Gerlic M, Kurowska-Stolarska M, Rainey AA, Pich D, McInnes IB, Hammerschmidt W, O'Neill LA, Masters SL. Cutting Edge: miR-223 and EBV miR-BART15 Regulate the NLRP3 Inflammasome and IL-1β Production. J Immunol. 2012 Oct 15;189(8):3795-9. doi: 10.4049/jimmunol.1200312. Epub 2012 Sep 14. PMID: 22984081

Correa RG, Khan PM, Askari N, Zhai D, Gerlic M, Brown B, Magnuson G, Spreafico R, Albani S, Sergienko E, Diaz PW, Roth GP, Reed JC. Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors. Chem Biol. 2011 Jul 29;18(7):825-32. PMID: 21802003

Yu E, Zhai D, Jin C, Gerlic M, Reed JC, Liddington R. Structural determinants of caspase-9 inhibition by the vaccinia virus protein, F1L. J Biol Chem. 2011 Sep 2;286(35):30748-58. Epub 2011 Jul 11. PMID: 21757755

Garrison JB, Correa RG, Gerlic M, Yip KW, Krieg A, Tamble CM, Shi R, Welsh K, Duggineni S, Huang Z, Ren K, Du C, Reed JC. ARTS and Siah collaborate in a pathway for XIAP degradation. Mol Cell. 2011 January;41(1):107-16. Epub 2010 Dec 23. PMID: 21185211

Yip KW, Godoi PH, Zhai D, Garcia X, Cellitti JF, Cuddy M, Gerlic M, Chen Y, Satterthwait A, Vasile S, Sergienko E, Reed JC. A TR3/Nur77 peptide-based high-throughput fluorescence polarization screen for small molecule Bcl-B inhibitors. J Biomol Screen. 2008 Aug;13(7):665-73. doi: 10.1177/1087057108320918. Epub 2008 Jul 14. PMID: 18626112

Gerlic M, Horowitz J, Farkash S, Horowitz S. The inhibitory effect of Mycoplasma fermentans on tumour necrosis factor (TNF)-alpha-induced apoptosis resides in the membrane lipoproteins. Cell Microbiol. 2007 Jan;9(1):142-53. Epub 2006 Aug 2. PMID: 16889623

Gerlic M, Horowitz J, Horowitz S. Mycoplasma fermentans inhibits tumor necrosis factor alpha-induced apoptosis in the human myelomonocytic U937 cell line. Cell Death Differ. 2004 Nov;11(11):1204-12. PMID: 15286682

Reviews

Silke J, Rickard JA, Gerlic M*. The diverse role of RIP kinases in necroptosis and inflammation. Nature Immunology, 2015 Jul;16(7):689-97. doi: 10.1038/ni.3206. Review. Erratum in: Nat Immunol. 2015 Aug;16(8):889. PMID: 26086143

Croker BA, Silke J, Gerlic M. Fight or flight: regulation of emergency hematopoiesis by pyroptosis and necroptosis, Current Opinion in Hematology, June, 2015, 22 (4), 293-301, DOI:10.1097/MOH.0000000000000148. PMID: 26049749

Gerlic M, Masters SL. A healthy appetite for Toxoplasma at the cellular level. Immunology and Cell Biology, Nevember 2014, 92 (10), 813-814. PMID: 25178968

Croker BA, O’Donnell JA, Gerlic M. Pyroptotic death storms and cytopenia. Current Opinion in Immunology (Invited review), 2014 Feb;26:128-37. doi: 10.1016/j.coi.2013.12.002. Epub 2013 Dec 22. PMID: 24556409

Haneklaus M*, Gerlic M*, O'Neill LA, Masters SL. miR-223: infection, inflammation and cancer, J Intern Med. 2013 Sep;274(3):215-26. doi: 10.1111/joim.12099. Epub 2013 Jun 25. *These authors contributed equally to this work. PMID: 23772809