I am a cellular immunologist specialising in infectious diseases. I trained at the University of Melbourne, before post-doctoral studies at Colorado State University, USA and the Centenary Institute where I established my own research group before taking up position at UTS in 2015. My current research projects are focused on identifying new biomarkers to aid the diagnosis of active TB disease and in dissecting the mechanisms by which macrophages control infection and regulate inflammation.
TB is still a major human pathogen despite the availability of antibiotics TB still kills around 1.5 million people a year, and growing drug resistance in TB strains is an increasing problem. New diagnostic tests to help identify TB patients and to monitor their progress during treatment to rapidly identify treatment non-responders are urgently required.
I have projects examining the response of macrophages, the natural host for TB. This work is focused on determining how TB infection modulates microRNA and microparticle expression and the biomarker potential of these molecules. I have active collaborations with colleagues in India, China and Australia collecting samples from TB patients and matched controls for analysis. I also have ongoing project looking at human macrophages and in vivo models of TB infection to dissect the mechanisms that regulate inflammation and granuloma formation.
Contribution to discipline:
I have been an active member of the Australasian Society for Immunology for over 20 years and in 2014 co-convened the ASI National meeting with 550 attendees. I am currently a member of the NSW ASI organizing committee having served as state councillor previously. I am an associate Editor for Immunology and Cell Biology and Frontiers in Microbiology and Immunology. I have served on NHMRC grant panels and regularly present my reserach at both National and International conferences .
Supervision of Students, Research Training and mentoring:
I have a strong commitment to student training and mentoring. I teach both undergraduate and postgraduates at The University of Technology Sydney, having taught at Sydney University and in the Australasian Society of Immunology teaching programs previously. I was the Post Graduate coordinator at the Centenary Institute from 2010-2014 and have mentored early career researchers at Sydney University and participates in the Science in Schools program.I have supervised numerous honours, PhD and Masters students.
Can supervise: YES
Development of new biomarkers to aid diagnosis of TB
Examination of the role of microRNA in regulation of immunity to TB infection
Inflammation and Granuloma Formation during TB infection
Role of TNF family members in regulating immunity to TB infection
I am the subject coordinator for Epidemiology and Public Health Microbiolgy. This is a great subject that explores numberous microbes of public health interest from the latest outbreaks of food poisoning to emerging pathogens and pandemics.
I am also the Program Director for the Masters of Science (Medical Biotechnology).
I teach into the Immunology subjects at both the second and third year and enjoying training new honours, PhD and Masters students.
Interested students are most welcome to contact me to discuss projects and positions within my group.
Efforts to reduce the global TB burden are hindered by the lack of simple, reliable non-sputum based diagnostics. To date studies investigating the biomarker potential of circulating host proteins and mRNA have not shown sufficient diagnostic utility. Recently, there has been increasing interest in circulating miRNA as a biomarker of TB disease. This review examined all published miRNA-TB biomarker studies to determine if a reproducible miRNA signature of TB disease could be elucidated. From 15 miRNA profiling studies, 894 miRNA differentially expressed between TB patients and healthy controls were identified in at least one study. Of these, 143 miRNA were validated by qPCR with 53 differentially expressed between TB patients and controls. Interestingly, only 8 of these miRNA were identified in 2 or more studies, and no consensus on a reproducible miRNA signature for identification of TB disease could be identified. TB disease is clearly associated with a wide breadth of differentially expressed miRNA. This review highlights our recent progress and the multiple factors, including environment, source of tissue, ethnicity and extent of TB disease that may influence miRNA expression. Coordinated efforts are required to validate identified targets in multiple populations to progress miRNA biomarker development.
Wright, K, Plain, K, Purdie, A, Saunders, BM & de Silva, K 2019, 'Biomarkers for Detecting Resilience against Mycobacterial Disease in Animals.', Infection and immunity, vol. 88, no. 1.View/Download from: UTS OPUS or Publisher's site
Paratuberculosis and bovine tuberculosis are two mycobacterial diseases of ruminants which have a considerable impact on livestock health, welfare, and production. These are chronic "iceberg" diseases which take years to manifest and in which many subclinical cases remain undetected. Suggested biomarkers to detect infected or diseased animals are numerous and include cytokines, peptides, and expression of specific genes; however, these do not provide a strong correlation to disease. Despite these advances, disease detection still relies heavily on dated methods such as detection of pathogen shedding, skin tests, or serology. Here we review the evidence for suitable biomarkers and their mechanisms of action, with a focus on identifying animals that are resilient to disease. A better understanding of these factors will help establish new strategies to control the spread of these diseases.
Barry, SE, Ellis, M, Yang, Y, Guan, G, Wang, X, Britton, WJ & Saunders, BM 2018, 'Identification of a plasma microRNA profile in untreated pulmonary tuberculosis patients that is modulated by anti-mycobacterial therapy.', The Journal of infection, vol. 77, no. 4, pp. 341-348.View/Download from: UTS OPUS or Publisher's site
microRNA expression profiles are of interest as a biomarker of tuberculosis (TB). How anti-TB therapy effects miRNA profiles is unknown and was examined.We identified 87 plasma miRNAs that were significantly modified in an exploratory group of 19 Chinese pulmonary TB (PTB) patients compared to 14 healthy controls. We selected 10 of these miRNAs for analysis in a cohort of 100 PTB patients prior to, and at one, two and six months during treatment.Five miRNAs were differentially expressed in PTB patients compared to controls at diagnosis; miRs -29a and -99b were up-regulated, whilst miRs -21, -146a and -652 were down-regulated. A combination of 5 miRNA distinguished TB from healthy controls with a sensitivity of 94%, a specificity of 88%, and an AUC of 0.976. Within one month of treatment, significant changes in miRs -29a, -99b, -26a and 146a levels occurred in successfully treated patients, although not all miRNAs returned to baseline by treatment completion.A 5-miRNA signature shows potential for development as a novel biomarker for TB disease with potential to predict response to treatment. The failure of all miRNA to return to baseline levels may reflect ongoing remodelling in the lung parenchyma that continues after completion of anti-TB therapy.
Saunders, BM, Rudnicka, C, Filipovska, A, Davies, S, Ward, N, Hricova, J, Schlaich, MP & Matthews, VB 2018, 'Shining LIGHT on the metabolic role of the cytokine TNFSF14 and the implications on hepatic IL-6 production.', Immunology and cell biology, vol. 96, no. 1, pp. 41-53.View/Download from: UTS OPUS or Publisher's site
The cytokine Tumor Necrosis Factor Superfamily member 14, TNFSF14 (or LIGHT), is a controversial player in numerous diseases. We investigated the role of endogenously expressed TNFSF14 in diet-induced obesity in vivo. Firstly, we studied the effects of Tnfsf14 ablation on the development of obesity, glucose intolerance, insulin resistance, steatosis, tissue inflammation, and mitochondrial respiration in the liver. Secondly, we examined the role of TNFSF14 expression in hematopoietic cells on obesity and insulin sensitivity. Male Tnfsf14 knockout (KO) and wild type mice were fed chow or high fat diet (HFD) for 12 weeks and were assessed for weight gain, glucose intolerance, insulin resistance, hepatosteatosis, mitochondrial dysfunction, and cytokine expression. Wild-type mice were also reconstituted with bone marrow cells from Tnfsf14 knockout mice and were fed chow or HFD for 12 weeks. These mice were examined for weight gain and insulin resistance. HFD fed mice had elevated circulating levels of serum TNFSF14. Liver and white adipose tissue are potential sources of this elevated TNFSF14. Tnfsf14 deficient mice displayed increased obesity, glucose intolerance, insulin resistance, hepatosteatosis, and mitochondrial dysfunction compared to control mice on a HFD. Hepatic cytokine profiling pointed to a potential novel role of decreased IL-6 in the metabolic disturbances in obesogenic Tnfsf14 knockout mice. Bone marrow cells from Tnfsf14 deficient mice appeared to promote diet-induced obesity, insulin resistance and reduced FGF21 levels in white adipose tissue and liver. Our novel data suggest that Tnfsf14 ablation exacerbates parameters of the metabolic syndrome under high fat feeding conditions and provides evidence to support the development of TNFSF14 agonists as potential therapeutics in diet-induced obesity.
Hare, NJ, Lee, LY, Loke, I, Britton, WJ, Saunders, BM & Thaysen-Andersen, M 2017, 'Mycobacterium tuberculosis Infection Manipulates the Glycosylation Machinery and the N-Glycoproteome of Human Macrophages and Their Microparticles.', Journal of Proteome Research, vol. 16, no. 1, pp. 247-263.View/Download from: UTS OPUS or Publisher's site
Tuberculosis (TB) remains a prevalent and lethal infectious disease. The glycobiology associated with Mycobacterium tuberculosis infection of frontline alveolar macrophages is still unresolved. Herein, we investigated the regulation of protein N-glycosylation in human macrophages and their secreted microparticles (MPs) used for intercellular communication upon M. tb infection. LC-MS/MS-based proteomics and glycomics were performed to monitor the regulation of glycosylation enzymes and receptors and the N-glycome in in vitro-differentiated macrophages and in isolated MPs upon M. tb infection. Infection promoted a dramatic regulation of the macrophage proteome. Most notably, significant infection-dependent down-regulation (4-26 fold) of 11 lysosomal exoglycosidases, e.g., β-galactosidase, β-hexosaminidases and α-/β-mannosidases, was observed. Relative weak infection-driven transcriptional regulation of these exoglycosidases and a stronger augmentation of the extracellular hexosaminidase activity demonstrated that the lysosome-centric changes may originate predominantly from infection-induced secretion of the lysosomal content. The macrophages showed heterogeneous N-glycan profiles and displayed significant up-regulation of complex-type glycosylation and concomitant down-regulation of paucimannosylation upon infection. Complementary intact N-glycopeptide analysis supported a subcellular-specific manipulation of the glycosylation machinery and altered glycosylation patterns of lysosomal N-glycoproteins within infected macrophages. Interestingly, the corresponding macrophage-derived MPs displayed unique N-glycome and proteome signatures supporting a preferential packaging from plasma membranes. The MPs were devoid of infection-dependent N-glycosylation signatures, but interestingly displayed increased levels of the glyco-initiating oligosaccharyltransferase complex and associated α-glucosidases that correlated with increased formation, N-glycan precursor levels and N-...
Nagalingam, G, Vinuesa, CG, Britton, WJ & Saunders, BM 2017, 'Modulation of Roquin Function in Myeloid Cells Reduces Mycobacterium tuberculosis-Induced Inflammation.', Journal of immunology (Baltimore, Md. : 1950), vol. 199, no. 5, pp. 1796-1804.View/Download from: UTS OPUS or Publisher's site
Damaging inflammation is a hallmark of Mycobacterium tuberculosis infection, and understanding how this is regulated is important for the development of new therapies to limit excessive inflammation. The E3 ubiquitin ligase, Roquin, is involved in immune regulation; however, its role in immunity to M. tuberculosis is unknown. To address this, we infected mice with a point mutation in Roquin1/Rc3h1 (sanroque). Aerosol-infected sanroque mice showed enhanced control of M. tuberculosis infection associated with delayed bacterial dissemination and upregulated TNF production in the lungs after 2 wk. However, this early control of infection was not maintained, and by 8 wk postinfection sanroque mice demonstrated an increased bacterial burden and dysregulated inflammation in the lungs. As the inflammation in the lungs of the sanroque mice could have been influenced by emerging autoimmune conditions that are characteristic of the mice aging, the function of Roquin was examined in immune cell subsets in the absence of autoimmune complications. M. bovis bacillus Calmette-Guérin-primed sanroque T cells transferred into Rag1-/- mice provided equivalent protection in the spleen and liver. Interestingly, the transfer of mycobacteria-specific (P25 CD4+ TCR transgenic) wild-type spleen cells into sanroqueRag1-/- mice actually led to enhanced protection with reduced bacterial load, decreased chemokine expression, and reduced inflammation in the lungs compared with transfers into Rag1-/- mice expressing intact Roquin. These studies suggest that modulation of Roquin in myeloid cells may reduce both inflammation and bacterial growth during the chronic phase of M. tuberculosis infection.
Sierro, F, Evrard, M, Rizzetto, S, Melino, M, Mitchell, AJ, Florido, M, Beattie, L, Walters, SB, Tay, SS, Lu, B, Holz, LE, Roediger, B, Wong, YC, Warren, A, Ritchie, W, McGuffog, C, Weninger, W, Le Couteur, DG, Ginhoux, F, Britton, WJ, Heath, WR, Saunders, BM, McCaughan, GW, Luciani, F, MacDonald, KPA, Ng, LG, Bowen, DG & Bertolino, P 2017, 'A Liver Capsular Network of Monocyte-Derived Macrophages Restricts Hepatic Dissemination of Intraperitoneal Bacteria by Neutrophil Recruitment', IMMUNITY, vol. 47, no. 2, pp. 374-+.View/Download from: UTS OPUS or Publisher's site
Donnelly, S, Huston, WM, Johnson, M, Tiberti, N, Saunders, B, O'Brien, B, Burke, C, Labbate, M & Combes, V 2017, 'Targeting the master regulator mTOR: a new approach to prevent the neurological of consequences of parasitic infections?', Parasites & Vectors, vol. 10, no. 1, pp. 1-6.View/Download from: UTS OPUS or Publisher's site
A systematic analysis of 240 causes of death in 2013 revealed that parasitic diseases were responsible for more than one million deaths. The vast majority of these fatalities resulted from protozoan infections presenting with neurological sequelae. In the absence of a vaccine, development of effective therapies is essential to improving global public health. In 2015, an intriguing strategy to prevent cerebral malaria was proposed by Gordon et al. 2015 mBio, 6:e00625. Their study suggested that inhibition of the mammalian target of rapamycin prevented experimental cerebral malaria by blocking the damage to the blood brain barrier and stopping the accumulation of parasitized red blood cells and T cells in the brain. Here, we hypothesize that the same therapeutic strategy could be adopted for other protozoan infections with a brain tropism, to prevent cerebral parasitosis by limiting pathogen replication and preventing immune mediated destruction of brain tissue.
Kapetanovic, R, Bokil, NJ, Achard, ME, Ong, CL, Peters, KM, Stocks, CJ, Phan, MD, Monteleone, M, Schroder, K, Irvine, KM, Saunders, BM, Walker, MJ, Stacey, KJ, McEwan, AG, Schembri, MA & Sweet, MJ 2016, 'Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages.', FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol. 30, no. 5, pp. 1901-1912.View/Download from: UTS OPUS or Publisher's site
We aimed to characterize antimicrobial zinc trafficking within macrophages and to determine whether the professional intramacrophage pathogen Salmonella enterica serovar Typhimurium (S Typhimurium) subverts this pathway. Using both Escherichia coli and S Typhimurium, we show that TLR signaling promotes the accumulation of vesicular zinc within primary human macrophages. Vesicular zinc is delivered to E. coli to promote microbial clearance, whereas S. Typhimurium evades this response via Salmonella pathogenicity island (SPI)-1. Even in the absence of SPI-1 and the zinc exporter ZntA, S Typhimurium resists the innate immune zinc stress response, implying the existence of additional host subversion mechanisms. We also demonstrate the combinatorial antimicrobial effects of zinc and copper, a pathway that S. Typhimurium again evades. Our use of complementary tools and approaches, including confocal microscopy, direct assessment of intramacrophage bacterial zinc stress responses, specific E. coli and S Typhimurium mutants, and inductively coupled plasma mass spectroscopy, has enabled carefully controlled characterization of this novel innate immune antimicrobial pathway. In summary, our study provides new insights at the cellular level into the well-documented effects of zinc in promoting host defense against infectious disease, as well as the complex host subversion strategies employed by S Typhimurium to combat this pathway.-Kapetanovic, R., Bokil, N. J., Achard, M. E. S., Ong, C.-L. Y., Peters, K. M., Stocks, C. J., Phan, M.-D., Monteleone, M., Schroder, K., Irvine, K. M., Saunders, B. M., Walker, M. J., Stacey, K. J., McEwan, A. G., Schembri, M. A., Sweet, M. J. Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages.
Barry, SE, Chan, B, Ellis, M, Yang, Y, Plit, ML, Guan, G, Wang, X, Britton, WJ & Saunders, BM 2015, 'Identification of miR-93 as a suitable miR for normalizing miRNA in plasma of tuberculosis patients', JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, vol. 19, no. 7, pp. 1606-1613.View/Download from: UTS OPUS or Publisher's site
Hare, NJ, Chan, B, Chan, E, Kaufman, KL, Britton, WJ & Saunders, BM 2015, 'Microparticles released from Mycobacterium tuberculosis-infected human macrophages contain increased levels of the type I interferon inducible proteins including ISG15', PROTEOMICS, vol. 15, no. 17, pp. 3020-3029.View/Download from: UTS OPUS or Publisher's site
Fox, GJ, Sy, DN, Nhung, NV, Yu, B, Ellis, MK, Van Hung, N, Cuong, NK, Thi Lien, L, Marks, GB, Saunders, BM & Britton, WJ 2014, 'Polymorphisms of SP110 are associated with both pulmonary and extra-pulmonary tuberculosis among the Vietnamese.', PLoS ONE, vol. 9, no. 7, pp. 1-9.View/Download from: UTS OPUS or Publisher's site
Tuberculosis (TB) is an infectious disease that remains a major cause of morbidity and mortality worldwide, yet the reasons why only 10% of people infected with Mycobacterium tuberculosis go on to develop clinical disease are poorly understood. Genetically determined variation in the host immune response is one factor influencing the response to M. tuberculosis. SP110 is an interferon-responsive nuclear body protein with critical roles in cell cycling, apoptosis and immunity to infection. However association studies of the gene with clinical TB in different populations have produced conflicting results.To examine the importance of the SP110 gene in immunity to TB in the Vietnamese we conducted a case-control genetic association study of 24 SP110 variants, in 663 patients with microbiologically proven TB and 566 unaffected control subjects from three tertiary hospitals in northern Vietnam.Five SNPs within SP110 were associated with all forms of TB, including four SNPs at the C terminus (rs10208770, rs10498244, rs16826860, rs11678451) under a dominant model and one SNP under a recessive model, rs7601176. Two of these SNPs were associated with pulmonary TB (rs10208770 and rs16826860) and one with extra-pulmonary TB (rs10498244).SP110 variants were associated with increased susceptibility to both pulmonary and extra-pulmonary TB in the Vietnamese. Genetic variants in SP110 may influence macrophage signaling responses and apoptosis during M. tuberculosis infection, however further research is required to establish the mechanism by which SP110 influences immunity to tuberculosis infection.
Walters, SB, Kieckbusch, J, Nagalingam, G, Swain, A, Latham, SL, Grau, GER, Britton, WJ, Combes, V & Saunders, BM 2013, 'Microparticles from Mycobacteria-Infected Macrophages Promote Inflammation and Cellular Migration', JOURNAL OF IMMUNOLOGY, vol. 190, no. 2, pp. 669-677.View/Download from: UTS OPUS or Publisher's site
Blumenthal, A, Nagalingam, G, Huch, JH, Walker, L, Guillemin, GJ, Smythe, GA, Ehrt, S, Britton, WJ & Saunders, BM 2012, 'M-tuberculosis Induces Potent Activation of IDO-1, but This Is Not Essential for the Immunological Control of Infection', PLOS ONE, vol. 7, no. 5.View/Download from: UTS OPUS or Publisher's site
Beham, AW, Puellmann, K, Laird, R, Fuchs, T, Streich, R, Breysach, C, Raddatz, D, Oniga, S, Peccerella, T, Findeisen, P, Kzhyshkowska, J, Gratchev, A, Schweyer, S, Saunders, B, Wessels, JT, Moebius, W, Keane, J, Becker, H, Ganser, A, Neumaier, M & Kaminski, WE 2011, 'A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis', PLOS PATHOGENS, vol. 7, no. 11.View/Download from: UTS OPUS or Publisher's site
Bokil, NJ, Totsika, M, Carey, AJ, Stacey, KJ, Hancock, V, Saunders, BM, Ravasi, T, Ulett, GC, Schembri, MA & Sweet, MJ 2011, 'Intramacrophage survival of uropathogenic Escherichia coli: Differences between diverse clinical isolates and between mouse and human macrophages', IMMUNOBIOLOGY, vol. 216, no. 11, pp. 1164-1171.View/Download from: UTS OPUS or Publisher's site
Gu, BJ, Saunders, BM, Petrou, S & Wiley, JS 2011, 'P2X(7) Is a Scavenger Receptor for Apoptotic Cells in the Absence of Its Ligand, Extracellular ATP', JOURNAL OF IMMUNOLOGY, vol. 187, no. 5, pp. 2365-2375.View/Download from: UTS OPUS or Publisher's site
Stanley, AC, Rivera, FDL, Haque, A, Sheel, M, Zhou, Y, Amante, FH, Bunn, PT, Randall, LM, Pfeffer, K, Scheu, S, Hickey, MJ, Saunders, BM, Ware, C, Hill, GR, Tamada, K, Kaye, PM & Engwerda, CR 2011, 'Critical Roles for LIGHT and Its Receptors in Generating T Cell-Mediated Immunity during Leishmania donovani Infection', PLOS PATHOGENS, vol. 7, no. 10.View/Download from: UTS OPUS or Publisher's site
Miller, CM, Boulter, NR, Fuller, SJ, Zakrzewski, AM, Lees, MP, Saunders, BM, Wiley, JS & Smith, NC 2011, 'The Role of the P2X(7) Receptor in Infectious Diseases', PLOS PATHOGENS, vol. 7, no. 11.View/Download from: UTS OPUS or Publisher's site
Gu, BJ, Saunders, BM, Jursik, C & Wiley, JS 2010, 'The P2X(7)-nonmuscle myosin membrane complex regulates phagocytosis of nonopsonized particles and bacteria by a pathway attenuated by extracellular ATP', BLOOD, vol. 115, no. 8, pp. 1621-1631.View/Download from: Publisher's site
Kuang, Z, Lewis, RS, Curtis, JM, Zhan, Y, Saunders, BM, Babon, JJ, Kolesnik, TB, Low, A, Masters, SL, Willson, TA, Kedzierski, L, Yao, S, Handman, E, Norton, RS & Nicholson, SE 2010, 'The SPRY domain-containing SOCS box protein SPSB2 targets iNOS for proteasomal degradation', JOURNAL OF CELL BIOLOGY, vol. 190, no. 1, pp. 129-141.View/Download from: Publisher's site
Musicki, K, Briscoe, H, Britton, WJ & Saunders, BM 2010, 'LIGHT contributes to early but not late control of Mycobacterium tuberculosis infection', INTERNATIONAL IMMUNOLOGY, vol. 22, no. 5, pp. 353-358.View/Download from: Publisher's site
Wozniak, TM, Saunders, BM, Ryan, AA & Britton, WJ 2010, 'Mycobacterium bovis BCG-Specific Th17 Cells Confer Partial Protection against Mycobacterium tuberculosis Infection in the Absence of Gamma Interferon', INFECTION AND IMMUNITY, vol. 78, no. 10, pp. 4187-4194.View/Download from: Publisher's site
Hagge, DA, Saunders, BM, Ebenezer, GJ, Ray, NA, Marks, VT, Britton, WJ, Krahenbuhl, JL & Adams, LB 2009, 'Lymphotoxin-alpha and TNF Have Essential but Independent Roles in the Evolution of the Granulomatous Response in Experimental Leprosy', AMERICAN JOURNAL OF PATHOLOGY, vol. 174, no. 4, pp. 1379-1389.View/Download from: Publisher's site
Miu, J, Mitchell, AJ, Mueller, M, Carter, SL, Manders, PM, McQuillan, JA, Saunders, BM, Ball, HJ, Lu, B, Campbell, LL & Hunt, NH 2008, 'Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency', JOURNAL OF IMMUNOLOGY, vol. 180, no. 2, pp. 1217-1230.View/Download from: Publisher's site
Britton, WJ, Fernando, SL, Saunders, BM, Sluyter, R & Wiley, JS 2007, 'The genetic control of susceptibility to Mycobacterium tuberculosis', Novartis Foundation Symposium, vol. 281, pp. 79-89.
Mycobacterium tuberculosis is one of the most successful human pathogens, surviving in latent foci of infection in one third of humanity, yet causing lung necrosis in sufficient individuals to ensure its transmission. Each stage of the host response to M. tuberculosis is under genetic control, including the initial encounter with mycobacteria by macrophages, epithelial cells and dendritic cells in the lung, induction of the inductive T cell response, and killing by activated macrophages within granulomas. Although environmental factors are important determinants of progression to disease, there is a genetic component underlying susceptibility to tuberculosis (TB), the basis of which may vary in different populations. Recent studies using a variety of methods have defi ned a number of susceptibility alleles for the development of active TB. Many of these influence macrophage responses to mycobacteria. We have studied the influence of loss of function polymorphisms in the human P2X7 gene on the capacity of macrophages to kill M. tuberculosis. Activation of the P2X7 receptor, an ATP-gated Ca2+ channel, leads to the formation of pores, the activation of phospholipase D, and the induction of apoptosis with death of the infecting mycobacteria. Macrophages from subjects who are heterozygote, homozygote or compound heterozygote for these polymorphisms fail to undergo apoptosis and show partial or complete inhibition of mycobacterial killing. One of these non-functioning polymorphisms was significantly associated with increased susceptibility to TB disease, particularly extrapulmonary disease, in two unrelated cohorts of TB patients. Insights into the genetic regulation of susceptibility to human TB may identify novel methods for controlling latent M. tuberculosis and reducing the burden of tuberculosis. Copyright © Novartis Foundation 2007.
Fernando, SL, Saunders, BM, Sluyter, R, Skarratt, KK, Goldberg, H, Marks, GB, Wiley, JS & Britton, WJ 2007, 'A polymorphism in the P2X(7) gene increases susceptibility to extrapulmonary tuberculosis', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 175, no. 4, pp. 360-366.View/Download from: Publisher's site
Musicki, K, Briscoe, H, Tran, S, Britton, WJ & Saunders, BM 2006, 'Differential requirements for soluble and transmembrane tumor necrosis factor in the immunological control of primary and secondary Listeria monocytogenes infection', INFECTION AND IMMUNITY, vol. 74, no. 6, pp. 3180-3189.View/Download from: Publisher's site
Shemon, AN, Sluyter, R, Fernando, SL, Clarke, AL, Dao-Ung, LP, Skarratt, KK, Saunders, BM, Khai, ST, Gu, BJ, Fuller, SJ, Britton, WJ, Petrou, S & Wiley, JS 2006, 'A Thr357 to Ser polymorphism in homozygous and compound heterozygous subjects causes absent or reduced P2X7 function and impairs ATP-induced mycobacterial killing by macrophages', Journal of Biological Chemistry, vol. 281, no. 4, pp. 2079-2086.View/Download from: Publisher's site
The P2X7 receptor is a ligand-gated cation channel that is highly expressed on mononuclear leukocytes and that mediates ATP-induced apoptosis and killing of intracellular pathogens. There is a wide variation in P2X7 receptor function between subjects, explained in part by four loss-of-function polymorphisms (R307Q, E496A, I568N, and a 5′-intronic splice site polymorphism), as well as rare mutations. In this study, we report the allele frequencies of 11 non-synonymous P2X7 polymorphisms and describe a fifth loss-of-function polymorphism in the gene (1096C → G), which changes Thr357 to Ser (T357S) with an allele frequency of 0.08 in the Caucasian population. P2X7 function was measured by ATP-induced ethidium+ influx into peripheral blood lymphocytes and monocytes and, when compared with wild-type subjects, was reduced to 10-65% in heterozygotes, 1-18% in homozygotes, and 0-10% in compound heterozygotes carrying T357S and a second loss-of-function polymorphism. Overexpression of the T357S mutant P2X7 in either HEK-293 cells or Xenopus oocytes gave P2X7 function of ∼50% that of wild-type constructs. Differentiation of monocytes to macrophages, which also up-regulates P2X 7, restored P2X7 function to near normal in cells heterozygous for T357S and to a value 50-65% of wild-type in cells homozygous for T357S or compound heterozygous for T357S/E496A. However, macrophages from subjects that are compound heterozygous for either T357S/R307Q or T357S/stop codon had near-to-absent P2X7 function. These functional deficits induced by T357S were paralleled by impaired ATP-induced apoptosis and mycobacteria killing in macrophages from these subjects. Lymphocytes, monocytes, and macrophages from subjects homozygous for T357S or compound heterozygous for T357S and a second loss-of-function allele have reduced or absent P2X 7 receptor function. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Shemon, AN, Sluyter, R, Fernando, SL, Clarke, AL, Dao-Ung, LP, Skarratt, KK, Saunders, BM, Tan, KS, Gu, BJ, Fuller, SJ, Britton, WJ, Petrou, S & Wiley, JS 2006, 'A Thr(357) to Ser polymorphism in homozygous and compound heterozygous subjects causes absent or reduced P2X(7) function and impairs ATP-induced mycobacterial killing by macrophages', JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 281, no. 4, pp. 2079-2086.View/Download from: Publisher's site
Fernando, SL, Saunders, BM, Sluyter, R, Skarratt, KK, Wiley, JS & Britton, WJ 2005, 'Gene dosage determines the negative effects of polymorphic alleles of the P2X(7) receptor on adenosine triphosphate-mediated killing of mycobacteria by human macrophages', JOURNAL OF INFECTIOUS DISEASES, vol. 192, no. 1, pp. 149-155.View/Download from: Publisher's site
Roach, DR, Briscoe, H, Saunders, BA & Britton, WJ 2005, 'Independent protective effects for tumor necrosis factor and lymphotoxin alpha in the host response to Listeria monocytogenes infection', INFECTION AND IMMUNITY, vol. 73, no. 8, pp. 4787-4792.View/Download from: Publisher's site
Saunders, BM, Tran, S, Ruuls, S, Sedgwick, JD, Briscoe, H & Britton, WJ 2005, 'Transmembrane TNF is sufficient to initiate cell migration and granuloma formation and provide acute, but not long-term, control of Mycobacterium tuberculosis infection', JOURNAL OF IMMUNOLOGY, vol. 174, no. 8, pp. 4852-4859.View/Download from: Publisher's site
Pinto, R, Saunders, BM, Camacho, LR, Britton, WJ, Gicquel, B & Triccas, JA 2004, 'Mycobacterium tuberculosis defective in phthiocerol dimycocerosate translocation provides greater protective immunity against tuberculosis than the existing bacille Calmette-Guerin vaccine', JOURNAL OF INFECTIOUS DISEASES, vol. 189, no. 1, pp. 105-112.View/Download from: Publisher's site
Saunders, BM, Briscoe, H & Britton, WJ 2004, 'T cell-derived tumour necrosis factor is essential, but not sufficient, for protection against Mycobacterium tuberculosis infection', CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 137, no. 2, pp. 279-287.View/Download from: Publisher's site
Saunders, BM, Fernando, SL, Sluyter, R, Britton, WJ & Wiley, JS 2003, 'A loss-of-function polymorphism in the human P2X(7) receptor abolishes ATP-mediated killing of mycobacteria', JOURNAL OF IMMUNOLOGY, vol. 171, no. 10, pp. 5442-5446.View/Download from: Publisher's site
Saunders, BM, Dane, A, Briscoe, H & Britton, WJ 2002, 'Characterization of immune responses during infection with Mycobacterium avium strains 100, 101 and the recently sequenced 104', IMMUNOLOGY AND CELL BIOLOGY, vol. 80, no. 6, pp. 544-549.View/Download from: Publisher's site
Saunders, BM, Frank, AA, Orme, IM & Cooper, AM 2002, 'CD4 is required for the development of a protective granulomatous response to pulmonary tuberculosis', CELLULAR IMMUNOLOGY, vol. 216, no. 1-2, pp. 65-72.View/Download from: Publisher's site
Pearl, JE, Saunders, B, Ehlers, S, Orme, IM & Cooper, AM 2001, 'Inflammation and lymphocyte activation during mycobacterial infection in the interferon-γ-deficient mouse', Cellular Immunology, vol. 211, no. 1, pp. 43-50.View/Download from: Publisher's site
Interferon-γ is a pivotal cytokine in the protective response to tuberculosis. In its absence rampant bacterial growth results in tissue destruction and death. While macrophage activation is key, this pleiotropic cytokine has other secondary but significant roles. To investigate these roles, both intravenous and aerosol infection of the IFN-γ gene disrupted (GKO) mouse was performed. For the first time we describe the very similar growth of bacteria, during the initial phase of infection, between control and GKO mice. During this initial phase, however, very different histopathologic consequences between control and GKO mice were observed. Key observations included an early increased accumulation of granulocytes and a much more rapid and pronounced interstitial pneumonia in the GKO mice. As infection developed, GKO mice mounted an antigen-specific response; however, lymphocyte activation was much more rapid in these mice. Of interest is the fact that this increased rapidity occurred prior to significant differences in bacterial number. Taken together these data support a role for IFN-γ in limiting both initial cellular recruitment and acquired lymphocytic responses to mycobacterial infection. This role may be key in surviving the kind of chronic stimulatory disease caused by Mycobacterium tuberculosis. © 2001 Academic Press.
Roach, DR, Briscoe, H, Saunders, B, France, MP, Riminton, S & Britton, WJ 2001, 'Secreted lymphotoxin-α is essential for the control of an intracellular bacterial infection', Journal of Experimental Medicine, vol. 193, no. 2, pp. 239-246.View/Download from: UTS OPUS or Publisher's site
Although the essential role of tumor necrosis factor (TNF) in the control of intracellular bacterial infection is well established, it is uncertain whether the related cytokines lymphotoxin-α (LTα3) and lymphotoxin-β (LTβ) have independent roles in this process. Using C57Bl/6 mice in which the genes for these cytokines have been disrupted, we have examined the relative contribution of secreted LTα3 and membrane-bound LTβ in the host response to aerosol Mycobacterium tuberculosis infection. To overcome the lack of peripheral lymph nodes in LTα-/- and LTβ-/- mice, bone marrow chimeric mice were constructed. LTα-/- chimeras, which lack both secreted LTα3 and membrane-bound LTβ (LTα1β2 and LTα2β1), were highly susceptible and succumbed 5 wk after infection. LTβ-/- chimeras, which lack only the membrane-bound LTβ, controlled the infection in a comparable manner to wild-type (WT) chimeric mice. T cell responses to mycobacterial antigens and macrophage responses in LTα-/- chimeras were equivalent to those of WT chimeras, but in LTα-/- chimeras, granuloma formation was abnormal. LTα-/- chimeras recruited normal numbers of T cells into their lungs, but the lymphocytes were restricted to perivascular and peribronchial areas and were not colocated with macrophages in granulomas. Therefore, LTα3 is essential for the control of pulmonary tuberculosis, and its critical role lies not in the activation of T cells and macrophages per se but in the local organization of the granulomatous response.
Turner, J, Gonzalez-Juarrero, M, Saunders, BM, Brooks, JV, Marietta, P, Ellis, DL, Frank, AA & Cooper, AM 2001, 'Immunological basis for reactivation of tuberculosis in mice', INFECTION AND IMMUNITY, vol. 69, no. 5, pp. 3264-3270.View/Download from: Publisher's site
Pedrosa, J, Saunders, BM, Appelberg, R, Orme, IM, Silva, MT & Cooper, AM 2000, 'Neutrophils play a protective nonphagocytic role in systemic Mycobacterium tuberculosis infection of mice', INFECTION AND IMMUNITY, vol. 68, no. 2, pp. 577-583.View/Download from: Publisher's site
Saunders, BM & Cooper, AM 2000, 'Restraining mycobacteria: Role of granulomas in mycobacterial infections', IMMUNOLOGY AND CELL BIOLOGY, vol. 78, no. 4, pp. 334-341.View/Download from: Publisher's site
Saunders, BM, Frank, AA, Orme, IM & Cooper, AM 2000, 'Interleukin-6 induces early gamma interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection', INFECTION AND IMMUNITY, vol. 68, no. 6, pp. 3322-3326.View/Download from: Publisher's site
Saunders, BM, Frank, AA & Orme, IM 1999, 'Granuloma formation is required to contain bacillus growth and delay mortality in mice chronically infected with Mycobacterium tuberculosis', IMMUNOLOGY, vol. 98, no. 3, pp. 324-328.
Saunders, BM, Frank, AA, Cooper, AM & Orme, IM 1998, 'Role of gamma delta T cells in immunopathology of pulmonary Mycobacterium avium infection in mice', INFECTION AND IMMUNITY, vol. 66, no. 11, pp. 5508-5514.View/Download from: Publisher's site
Cooper, AM, Saunders, BM, D'Souza, CD, Frank, AA & Orme, IM 1997, 'Mycobacterium tuberculosis-driven processes in gene-disrupted mice', Bulletin de l'Institut Pasteur, vol. 95, no. 2, pp. 85-96.View/Download from: Publisher's site
Mice which have disrupted genes for important components of the immune system have been used to study the role of these components in the immune response to infection with Mycobacterium tuberculosis. This has resulted in the identification of interleukin-12 (IL12), interferon-γ (IFNγ), tumour necrosis factor-α (TNFα) and inducible nitric oxide synthase (iNOS) as being essential to the protective response. Less crucial but perhaps more intriguing roles for other molecules such as intercellular adhesion molecule (ICAM) and IL6 have also been suggested by this kind of analysis.
Saunders, BM & Cheers, C 1996, 'Increased lung cell cytotoxic but not bactericidal or phagocytic activity in Mycobacterium avium complex-infected mice', CELLULAR IMMUNOLOGY, vol. 171, no. 1, pp. 48-54.View/Download from: Publisher's site
Saunders, BM & Cheers, C 1996, 'Intranasal infection of beige mice with Mycobacterium avium complex: Role of neutrophils and natural killer cells', INFECTION AND IMMUNITY, vol. 64, no. 10, pp. 4236-4241.
SAUNDERS, BM & CHEERS, C 1995, 'INFLAMMATORY RESPONSE FOLLOWING INTRANASAL INFECTION WITH MYCOBACTERIUM-AVIUM COMPLEX - ROLE OF T-CELL SUBSETS AND GAMMA-INTERFERON', INFECTION AND IMMUNITY, vol. 63, no. 6, pp. 2282-2287.View/Download from: Publisher's site
SAUNDERS, BM, ZHAN, YF & CHEERS, C 1995, 'ENDOGENOUS INTERLEUKIN-12 IS INVOLVED IN RESISTANCE OF MICE TO MYCOBACTERIUM-AVIUM COMPLEX INFECTION', INFECTION AND IMMUNITY, vol. 63, no. 10, pp. 4011-4015.View/Download from: Publisher's site
Britton, WJ, Fernando, SL, Saunders, BM, Sluyter, R & Wiley, JS 2007, 'The genetic control of susceptibility to Mycobacterium tuberculosis' in Decoding the Genomic Control of Immune Reactions, pp. 79-92.View/Download from: Publisher's site
© Novartis Foundation 2007. All rights reserved. Mycobacterium tuberculosis is one of the most successful human pathogens, surviving in latent foci of infection in one third of humanity, yet causing lung necrosis in sufficient individuals to ensure its transmission. Each stage of the host response to M. tuberculosis is under genetic control, including the initial encounter with mycobacteria by macrophages, epithelial cells and dendritic cells in the lung, induction of the inductive T cell response, and killing by activated macrophages within granulomas. Although environmental factors are important determinants of progression to disease, there is a genetic component underlying susceptibility to tuberculosis (TB), the basis of which may vary in different populations. Recent studies using a variety of methods have defined a number of susceptibility alleles for the development of active TB. Many of these influence macrophage responses to mycobacteria. We have studied the influence of loss of function polymorphisms in the human P2X7 gene on the capacity of macrophages to kill M. tuberculosis. Activation of the P2X7 receptor, an ATP-gated Ca2+ channel, leads to the formation of pores, the activation of phospholipase D, and the induction of apoptosis with death of the infecting mycobacteria. Macrophages from subjects who are heterozygote, homozygote or compound heterozygote for these polymorphisms fail to undergo apoptosis and show partial or complete inhibition of mycobacterial killing. One of these non-functioning polymorphisms was significantly associated with increased susceptibility to TB disease, particularly extrapulmonary disease, in two unrelated cohorts of TB patients. Insights into the genetic regulation of susceptibility to human TB may identify novel methods for controlling latent M. tuberculosis and reducing the burden of tuberculosis.
Center for Research Excellence- TB
Prof Warwick Britton - Centenary Institute Sydney
Dr Patrick Bertolini- Centenary Insittute, Sydney
Prof Gobardhan Das, Jawaharlal Nehru University