Dr Thomas Naderer
Tel: +61-3-9902 9517
Fax: +61-3-9902 3726
Office: Rm 245, Level 2, Building 76 (STRIP 2)
Tull D, Heng J, Gooley PR, Naderer T*, McConville MJ*. Acylation-dependent and-independent membrane targeting and distinct functions of small myristoylated proteins (SMPs) in Leishmania major. Int J Parasitol. 2012 Mar;42(3):239-47.
After completing his undergraduate studies at the University Vienna, Austria, and a Masters at the University of Nottingham, UK, Thomas Naderer obtained his PhD from the University of Melbourne, Australia in 2004. He worked as a post-doctoral scientist in the laboratory of Prof Malcolm McConville (University of Melbourne) before joining the NHMRC Program on Cellular Microbiology headed by Prof Trevor Lithgow, Monash University. In 2012 he established the macrophage-pathogen interaction group with funding from the NHMRC.
Aim: The aim of the laboratory is to discover the molecular and cellular interactions that allow human pathogens to survive in macrophages.
Perspective: Macrophages are phagocytic (to engulf and digest) immune cells designed to kill invading microorganisms by employing a diverse arsenal of anti-microbial agents. They are part of the first line defence (innate immune response) but also initiate adaptive immunity. Despite that, several important human pathogens, including Legionella, Burkholderia, Mycobacteria and Leishmania survive long-term within specialized compartments or the cytosol of macrophages. Intracellular replication depends on efficient scavenging of essential nutrients, expression of diverse virulence factors and subversion of host cellular processes. Understanding the molecular interactions between macrophages and pathogens in more detail promises the discovery of novel anti-microbial drug targets.
Macrophages infected with the protozoan parasite Leishmania were stained with Hoechst (blue), tubulin (red) and LAMP-1 (green)
1. Characterization of effector molecules:
Intracellular pathogens express sophisticated machineries that facilitate the transfer of unique effector proteins into the cytoplasm of host macrophages. In particular, gram-negative bacteria have evolved several secretion systems that cross bacterial outer membranes. A major aim in the laboratory is to determine their localization and function using state of the art plat form technologies, including live-cell imaging, in close collaboration with other members of the host-pathogen unit. In particular, Legionella pneumophila exports around 10% (~300 proteins) of its proteome into the cytoplasm of host macrophages. We have recently shown that one of these effectors is targeted to the inner membrane of mitochondria as an ATP-carrier protein. The aim of this project is to characterize other effectors and to determine their role during infection.
Macrophages infected with GFP-expressing Legionella (green) were labelled with Mitotracker Red and live-cells imaged with a high-resolution microscope (N-SIM, Nikon)
2. Regulation of macrophage cell death pathways by bacteria
Macrophages are able to sense several pathogen associated patterns resulting in the activation of cell death pathways and secretion of pro-inflammatory cytokines. Conversely, bacterial pathogens have developed molecular mechanisms to subvert these pathways during intracellular growth. In the case of Legionella pneumophila at least two effectors have been shown to target cell death factors. The aim of this project is to determine how Legionella control cell death pathways and which pathways are required for successful replication in macrophages. For this, we utilize an array of transgenic mice that overexpress or lack individual cell death factors.
GFP-expressing Legionella were stained with FM4-64 and live-cells imaged with a high-resolution microscope (N-SIM, Nikon)
3. Bacterial escape from macrophages
Little is known how intracellular pathogens (trigger) escape from its host cells after completing their growth phase. While some pathogens express pore-forming toxins to facilitate rupture of the host membranes, others rely on host pathways for successful egress. Legionella infected macrophages have been shown to become increasingly apoptotic, suggesting that these bacteria activate distinct cell death pathway during escape. The aim of this project is to determine which cell death pathways are activated during Legionella egress by follow bacterial infections with live-cell imaging. Given that Legionella escape involves the rupture several membrane, the project aims to utilize correlative light and electron microscopy to determine the integrity of these membranes.
Dolezal P, Aili M, Tong J, Jiang JH, Marobbio CM, Lee SF, Schuelein R, Belluzzo S, Binova E, Mousnier A, Frankel G, Giannuzzi G, Palmieri F, Gabriel K, Naderer T, Hartland EL, Lithgow T. Legionella pneumophila secretes a mitochondrial carrier protein during infection. PLoS Pathog. 2012 Jan;8(1):e1002459.
Naderer T, Dandash O, McConville MJ. Calcineurin is required for Leishmania major stress response pathways and for virulence in the mammalian host. Mol Microbiol. 2011 Feb 14.
McConville MJ, Naderer T. Metabolic pathways required for the intracellular survival of Leishmania. Annu Rev Microbiol. 2011;65:543-61.
Naderer T*, Heng J*, McConville MJ. Evidence that intracellular stages of Leishmania major utilize amino sugars as a major carbon source. PLoS Pathog. 2010 Dec 23;6(12):e1001245.
Saunders EC, DE Souza DP, Naderer T, Sernee MF, Ralton JE, Doyle MA, Macrae JI, Chambers JL, Heng J, Nahid A, Likic VA, McConville MJ. Central carbon metabolism of Leishmania parasites. Parasitology. 2010 Aug;137(9):1303-13.
Tull D*, Naderer T*, Spurck T, Mertens HD, Heng J, McFadden GI, Gooley PR, McConville MJ. Membrane protein SMP-1 is required for normal flagellum function in Leishmania. J Cell Sci. 2010 Feb 15;123(Pt 4):544-54.
Naderer T, Wee E, McConville MJ. Role of hexosamine biosynthesis in Leishmania growth and virulence. Mol Microbiol. 2008 Aug;69(4):858-69. PMID: 18532982
Naderer T, McConville MJ. The Leishmania-macrophage interaction: a metabolic perspective. Cell Microbiol. 2008 Feb;10(2):301-8. Epub 2007 Dec 9. Review. PMID: 18070117
Naderer T, Ellis MA, Sernee MF, De Souza DP, Curtis J, Handman E, McConville MJ. Virulence of Leishmania major in macrophages and mice requires the gluconeogenic enzyme fructose-1,6-bisphosphatase. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5502-7. PMID:16569701