World TB Day Symposium: Countdown to 2015

World TB Day Symposium: Countdown to 2015

Monday, March 24, 2014

The New York Academy of Sciences

Tuberculosis (TB) is a curable infection that, by all rights, should be a disease of the past. However, despite Koch's discovery of Mycobacterium tuberculosis (Mtb) over 100 years ago, Mtb infects a third of the world's population and tragically remains the leading cause of death due to a bacterial infection, claiming the lives of nearly 1.3 million people in 2012. In 2013, the World Health Organization issued a report that highlighted both progress and delays associated with the United Nations Millennium Development Goals for TB control issued in 2001. Join us on World TB Day was we count down to the 2015 target deadline and explore regional efforts that are generating scientific insights and driving the development of novel diagnostic, therapeutic and vaccine-related tools.

*Reception to follow.

Registration Pricing

Member$30
Student/Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45


The Microbiology & Infectious Diseases Discussion Group is proudly supported by

  • Pfizer

Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


March 24, 2014

8:00 AM

Registration and Continental Breakfast

8:30 AM

Welcome and Introductory Remarks
Jennifer Henry, PhD, The New York Academy of Sciences

A Perspective on the 2011–2015 Global Plan to Stop TB: Outlook and Remaining Challenges
Jennifer A. Philips, MD, PhD NYU Langone Medical Center

Session I. TB – The Battlefield: Clinical Care

8:45 AM

Novel Regimens to Treat Tuberculosis – Great Hope in the Pipeline
Daniel E. Everitt, MD, TB Alliance

9:05 AM

TB Treatment
Jerrold J. Ellner, MD, Boston Medical Center

9:25 AM

Late-Breaking Abstract Presentation: Vitamin D Regulates Lipid Metabolism in Mycobacterium Tuberculosis Infection
Natalie Bruiners, PhD, New Jersey Medical School, Rutgers University

9:40 AM

Molecular Diagnostics to Improve Tuberculosis Treatment and to Prevent Drug Resistance
David Alland, MD, Rutgers New Jersey Medical School

10:00 AM

Coffee Break

Session II. Know Thine Enemy – Mycobacterium tuberculosis

10:30 AM

Understanding Essentiality
Kyu Rhee, MD, PhD, Weill Cornell Medical College

10:50 AM

Triglyceride Accumulation, Carbon Stress, and Virulence in Mycobacterium tuberculosis
Jessica C. Seeliger, PhD, Stony Brook University

11:10 AM

Late-Breaking Abstract Presentation: Molecular Profiling of M. tuberculosis Identifies Tuberculosinyl Nucleoside Products of the Virulence-Associated Enzyme Rv3378c
Emilie Layre, PhD, Brigham and Women’s Hospital, Harvard Medical School

11:25 AM

Signal Transduction across the M. tuberculosis Cell Envelope by RIP
Michael S. Glickman, MD, Memorial Sloan-Kettering Cancer Center

11:45 AM

Cyclic AMP (cAMP) Signaling in M. tuberculosis: Expanding the Circle
Kathleen A. McDonough, PhD, Wadsworth Center

12:05 PM

Late-Breaking Abstract Presentation: Mycobacterial Mixed Messages: Efficient Translation of Leadered and Leaderless Transcripts in Mycobacteria
Todd Gray, PhD, Wadsworth Center

12:20 PM

Lunch Break and Poster Session

Session III. At the Frontlines / Exchanging Blows – Mycobacterium tuberculosis and the Host

2:00 PM

Modulation of Host Resistance to Mycobacterium tuberculosis Infection by Helminths
Padmini Salgame, PhD, Rutgers New Jersey Medical School

2:20 PM

Genetic Predisposition to Severe Tuberculosis in Children
Stephanie Boisson-Dupuis, PhD, The Rockefeller University

2:40 PM

Proteasomal Regulation of Nitric Oxide Resistance in M. tuberculosis
Marie Samanovic, PhD, NYU Langone Medical Center

3:00 PM

Regulation of Iron Metabolism: An Essential Balancing Act Performed by Mycobacterium tuberculosis
G. Marcela Rodriguez, PhD, Rutgers New Jersey Medical School

3:20 PM

Late-Breaking Abstract Presentation: Ubiquilin 1 Recognizes Mycobacterial Determinants to Target Mycobacterium tuberculosis to the Autophagy Machinery
Erik Sakowski, New York University School of Medicine

3:35 PM

Coffee Break

Session IV. Winning the Battle Before it Begins: Protective Immunity

4:05 PM

T Cell Responses to TB Infection; IL-12Rb
Andrea M. Cooper, PhD, Trudeau Institute

4:25 PM

Late-Breaking Abstract Presentation: Cell-to-cell Antigen Transfer Without Pathogen Transfer Optimizes Priming of CD4 T cells
Smita Srivastava, PhD, New York University School of Medicine

4:40 PM

Unraveling the Tapestry of Immune Evasion by Mycobacterium tuberculosis
Steven A. Porcelli, MD, Albert Einstein College of Medicine

5:00 PM

Closing Remarks
Jessica C. Seeliger, PhD, Stony Brook University

Networking Reception

6:00 PM

Close

Speakers

Organizers

Takushi Kaneko, PhD

TB Alliance

Dr. Takushi Kaneko is Senior Research Fellow at TB Alliance (Global Alliance for TB Drug Development), a New York based not-for profit organization dedicated to the discovery and development of better, faster-acting, and affordable tuberculosis drugs. After obtaining a degree at the University of Michigan and conducting post-doctoral work at Harvard University, he spent most of his time in drug discovery research in Bristol-Myers Squibb and Pfizer in the areas of cancer chemotherapy, natural product discovery, and antibacterial agents.

Jennifer A. Philips, MD, PhD

NYU Langone Medical Center

Jennifer A. Philips received her medical and graduate training at the University of California, San Francisco. She completed clinical training in Internal Medicine and Infectious Diseases at Brigham and Women’s Hospital and Massachusetts General Hospital. She worked as a Translational Medicine Expert in the Infectious Disease Division at Novartis Institutes for BioMedical Research before starting her laboratory at the NYU School of Medicine. Her laboratory is interested in how Mycobacterium tuberculosis evades eradication by the host. She is a recipient of the Astellas Young Investigator Award from the Infectious Disease Society of America, the Clinical Scientist Development Award from the Doris Duke Charitable Foundation, and a grant from the Edward Mallinckrodt, Jr. Foundation.

Kyu Rhee, MD, PhD

Weill Cornell Medical College

Kyu Rhee is an Associate Professor in the Departments of Medicine and Microbiology & Immunology, and director of the Medical Research Track Residency Program at Weill Cornell Medical College. Dr. Rhee's interests focus on the intrabacterial biochemistry of M. tuberculosis and its application to the study of its pathogenicity and development of new diagnostic and therapeutic modalities.

Jessica C. Seeliger, PhD

Stony Brook University

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

David Alland, MD

Rutgers New Jersey Medical School

Dr. Alland received a BA in Psychology from Columbia College at Columbia University and an MD from The Columbia College of Physicians and Surgeons. He completed a Residency in Internal Medicine at Columbia Presbyterian Hospital (now The New York-Presbyterian Hospital) and then spent a year in London studying Tropical Medicine at the London School of Hygiene and Tropical Medicine where he received an MSc. in Clinical Tropical Medicine and a DTM&H. Dr. Alland performed a clinical fellowship in Infectious Disease at Montefiore Medical Center and then a research fellowship in the laboratory of Barry Bloom at the Albert Einstein College of Medicine. He stayed on at Albert Einstein/Montefiore as faculty and then moved to New Jersey Medical School – UMDNJ where he soon became Professor and Chief of the Division of Infectious Disease. He is currently also the Director of the Center for Emerging Pathogens and the Associate Dean for Clinical Research at New Jersey Medical School. Dr. Alland’s laboratory studies various aspects of drug tolerance and drug resistance in Mycobacterium tuberculosis with an emphasis on drug resistance evolution, resistance and tolerance mechanisms, and molecular diagnostics. His laboratory also studies tuberculosis phylogenetics and pathogenesis and has an active program in bacterial sepsis diagnostics. Dr. Alland developed the Xpert MTB/RIF assay, the first commercial assay that can detect the presence of M. tuberculosis and resistance to the drug rifampin directly from a clinical sputum sample in collaboration with Cepheid. His laboratory continues to work on M. tuberculosis molecular diagnostics including advanced applications of the Xpert assay. Dr. Alland has received numerous NIH grant awards and he currently serves as a member of the NIH CRFS study section and the ACTG Tuberculosis Transformational Science Committee.

Stephanie Boisson-Dupuis, PhD

The Rockefeller University

Dr. Stephanie Boisson-Dupuis received her PhD in 2002 from University Paris VII in France, where she studied the genetic susceptibility to mycobacterial diseases in the laboratory of Pr. Jean-Laurent Casanova. She discovered the first human STAT mutant, with dominant STAT1 mutations associated only with mycobacterial disease. She was a postdoctoral fellow with Pr. Pascale Cossart at the Pasteur Institute in France until 2006. She was granted a permanent research position at the INSERM institute in 2006 to continue working with Pr. Jean-Laurent Casanova and Laurent Abel on the genetic susceptibility to mycobacterial diseases (tuberculosis in particular). In 2008, she was appointed Senior Research Associate in the Laboratory of Human Genetics of Infectious Diseases at the Rockefeller University and continues to work on the genetic dissection of severe tuberculosis. Her areas of expertise include Mendelian genetics, molecular genetics and Infectious diseases.

Natalie Bruiners, PhD

New Jersey Medical School, Rutgers University

Natalie Bruiners attended the University of Stellenbosch, South Africa, where she received her BSc in Functional Human Biology in 2004. She obtained her Honours and Masters Degree at the Department of Human Genetics in 2007, investigating the potential genetic associations with preterm labour and other adverse pregnancy outcomes. She earned her PhD in Biomedical Sciences in 2013, investigating the role of ESX-1 secretion substrates in host-pathogen interactions and performing a case-control study to investigate specific genetic polymorphisms in a cohort of tuberculosis patients. Currently, she is continuing her research understanding the interaction between the tubercle bacilli and the macrophage at Public Health Research Institute, Rutgers University.

Andrea M. Cooper, PhD

Trudeau Institute

Dr. Cooper began her scientific career at The London School of Hygiene and Tropical Medicine where she described the interaction between macrophages and protozoan parasites of the genus Leishmania. Moving to the National Institutes of Health in Bethesda, Maryland, she expanded her investigation of leishmaniasis and leishmanial antigens to include the T-cell-mediated response of patients suffering from cutaneous, mucocutaneous and visceral forms of this disease. Dr. Cooper then moved to the Mycobacterial Research Labs at Colorado State University and began studying the protective immune response to Mycobacterium tuberculosis. She has been at the Trudeau Institute in Saranac Lake since 2002 and has continued to study the interaction between the vertebrate immune system and the chronically persistent macrophage recruiting Mycobacterium tuberculosis. She focuses on the function of antigen-specific T cells within the infected site and how the infected site regulates this function

Jerrold J. Ellner, MD

Boston Medical Center

Dr. Ellner is Professor and Chief of Infectious Diseases at Boston University School of Medicine and Boston Medical Center. He has studied the immunopathogenesis of TB and TB in HIV through research collaborations in Uganda and Brazil. Dr. Ellner has conducted clinical trials of the prevention of treatment of TB as well as the first HIV/AIDS Vaccine Trial in Africa. His research group was the first to show that TB accelerated the course of HIV infection by activating viral replication in latently infected cells. He was one of the principal architects of the Uganda-Case Western Reserve University Research Collaboration, a founding member of the Academic Alliance for AIDS Prevention and Care in Africa which developed the Infectious Diseases Institute at Makerere University, and the founding director of the TB Research Unit at Case Western Reserve University. He currently is PI of an International Collaboration for Infectious Diseases Research (ICIDR) program in Brazil and the TB - Clinical Diagnostics Research Consortium (CDRC). Dr. Ellner has authored more than 250 publications on TB and has trained a number of current academic leaders in infectious diseases.

Daniel E. Everitt, MD

TB Alliance

Dr. Everitt serves as Senior Medical Officer at the Global Alliance for TB Drug Development (TB Alliance). The TB Alliance is a non-profit Product Development Partnership that develops new treatments for tuberculosis through partnership with government and private funding sources, academic experts and pharmaceutical companies. Prior to joining the TB Alliance, Dr. Everitt spent 10 years in Johnson & Johnson’s pharmaceutical sector. There, he served in various roles, including as Vice President and Global Head of Clinical Pharmacology and Experimental Medicine at Johnson & Johnson Pharmaceutical Research and Development, and as Vice President of Safety Governance. Before working at Johnson & Johnson, Dr. Everitt spent 10 years in clinical research and development at SmithKline Beecham Pharmaceuticals. For six years, he was an Investigator in the Clinical Pharmacology Research Unit based at the University of Pennsylvania, and subsequently led Phase 2-4 development projects based in Harlow, United Kingdom, in the areas of neurosciences and anti-infectives.

Dr. Everitt gained his undergraduate degree from Duke University and his medical degree from Harvard Medical School. After an Internal Medicine residency at the Massachusetts General Hospital, he was a Fellow at Harvard in Geriatric Medicine and Clinical Epidemiology. Dr. Everitt is Board Certified in Internal Medicine, Geriatric Medicine and Clinical Pharmacology. He served on the faculty of departments of medicine at Harvard Medical School and at the University of Pennsylvania. In 2011, Dr. Everitt completed training and received a Diploma in Tropical Medicine and Hygiene from the London School of Hygiene and Tropical Medicine. Just prior to joining the TB Alliance, Dr. Everitt spent several months as a volunteer physician working in mission hospitals in Kenya. He is an author or co-author of 50 publications in peer-reviewed journals in the fields of Clinical Pharmacology and Pharmacoepidemiology.

Michael S. Glickman, MD

Memorial Sloan-Kettering Cancer Center

Dr. Michael S. Glickman is a Member in the Immunology Program and Attending Physician on the Infectious Diseases Service, both at Memorial Sloan Kettering Cancer Center. He is also Professor of Medicine, Immunology and Microbial Pathogenesis, and Molecular Biology at Weill Cornell Medical College. He is the incumbent of the Alfred Sloan Chair at Memorial Sloan Kettering Cancer Center. Dr. Glickman’s interests include signal transduction across the M. tuberculosis cell envelope, DNA repair, and the biosynthesis and pathogenic function of the M. tuberculosis cell envelope.

Todd Gray, PhD

Wadsworth Center

Todd Gray is a research scientist at the New York State Department of Health’s Wadsworth Center, and he is a faculty member for the University of Albany School of Public Health as well as for the Wadsworth’s Masters in Laboratory Sciences Program.  He develops functional genomic approaches to mycobacterial biology through the use of the experimentally tractable Mycobacterium smegmatis. Dr. Gray earned his doctorate in developmental gene regulation with Francis Collins at the University of Michigan and further broadened his expertise to include epigenetics and poxvirology before addressing the challenges of mycobacteriology. Dr. Gray’s research is focused on assigning functions to the many conserved unannotated genes that comprise mycobacterial genomes, and on defining horizontal gene transfer events that have shaped those genomes.

Kathleen A. McDonough, PhD

Wadsworth Center

Dr. McDonough is Deputy Director of Division of Infectious Diseases at the Wadsworth Center, New York State Department of Health and Professor of Biomedical Sciences at the University at Albany School of Public Health. Dr. McDonough is also Director of the Biodefense and Emerging Infections Training Program for graduate students and postdoctoral fellows at UAlbany and Wadsworth Center. Her research on the molecular pathogenesis of Mycobacterium tuberculosis focuses on the bacterium's gene regulatory responses to host-associated environments and the factors that control these responses. Dr. McDonough obtained her doctorate in Microbiology and Immunology from Stanford University School of Medicine, followed by training on tuberculosis pathogenesis as a Howard Hughes Medical Institute Postdoctoral Fellow at the Albert Einstein College of Medicine. Dr. McDonough's research program at Wadsworth Center is supported by National Institutes of Health, and she has been recognized on several occasions for her 'exceptional contributions to the NYS Department of Health'.

Steven A. Porcelli, MD

Albert Einstein College of Medicine

Dr. Steven Porcelli received an M.D. degree in 1984 from Yale University, and completed a medical residency at Temple University Hospital in 1987. He was fellow and then junior faculty member in the Division of Rheumatology, Immunology and Allergy at the Brigham and Women’s Hospital in Boston. As a research fellow and Assistant Professor at Harvard Medical School in the 1990’s, he pioneered studies on the CD1 antigen presentation pathway and lipid antigen recognition by T cells. These studies led him into the area of tuberculosis research, with a major emphasis on antigen presentation and T cell responses in Mycobacterium tuberculosis infection. In 2000, he was recruited as Irene Diamond Associate Professor in Immunology to Albert Einstein College of Medicine in Bronx, N.Y., and was subsequently appointed as Murray and Evelyne Weinstock Professor in the Department of Microbiology and Immunology. He is also Scientific Director of the Flow Cytometry Core Laboratories at Einstein. His laboratory has focused for the past decade on uncovering the immune evasion mechanisms of M. tuberculosis with the goal of rationally designing improved vaccines. Together with colleagues at Einstein, he has identified genes of M. tuberculosis that contribute to evasion of cell-mediated immunity, and is working to create new attenuated strains of mycobacteria that more effectively induce protective immunity against tuberculosis than the existing BCG vaccine.

Kyu Rhee, MD, PhD

Weill Cornell Medical College

Kyu Rhee is an Associate Professor in the Departments of Medicine and Microbiology & Immunology, and director of the Medical Research Track Residency Program at Weill Cornell Medical College. Dr. Rhee's interests focus on the intrabacterial biochemistry of M. tuberculosis and its application to the study of its pathogenicity and development of new diagnostic and therapeutic modalities.

G. Marcela Rodriguez, PhD

Rutgers New Jersey Medical School

I conducted undergraduate Studies in Bacteriology and Immunology in Bogota, Colombia in the “Universidad Javeriana”. I came to the USA to conduct my graduate studies. I worked for two years in the laboratory of Stephanie Diment as a research assistant working in antigen processing and presentation in the context of class II MHC molecules (and studying very hard to pass the GRE exam) and enter the graduate program at NYU. In 1999, I received a Ph.D in Microbiology from NYU. I did my thesis project studying iron regulation in Mycobacterium tuberculosis, in the laboratory of Dr. Issar Smith at the Public Health Research Institute. I stayed with Dr. Smith for a long post doc and continue my work on iron metabolism in Mtb. In 2007, I became Assistant professor at PHRI, at that time part of UMDNJ now, part of Rutgers the State University of New Jersey.

Erik Sakowski

NYU School of Medicine

Erik Sakowski graduated from Rutgers University with a B.S in Biotechnology in 2009. He is currently a microbiology graduate student in the laboratory of Dr. Jennifer Philips at NYU School of Medicine studying how Mycobacterium tuberculosis is recognized by the host.

Padmini Salgame, PhD

Rutgers New Jersey Medical School

Dr. Padmini Salgame, PhD is tenured Professor in the Department of Medicine, Division of Infectious Diseases and the Centre for Emerging Pathogens at Rutgers, New Jersey Medical School. Dr. Salgame is Director of the MD/PhD program and she also directs the MD with thesis and the Physician-Scientist Skills Programs. The research in the Salgame laboratory includes: i) Regulation of innate and adaptive immune response to M. tuberculosis by Toll-like receptors; ii) Impact of Helminths on immunity and host resistance to TB; iii) Identifying Biomarkers of protection and progression to TB disease. Dr. Salgame has served on several NIH peer-review study sections. She is a member of the Editorial Board for Infection and Immunity and Guest Editor for PLOS Pathogens.

Marie Samanovic, PhD

NYU Langone Medical Center

Dr. Marie Samanovic is currently a post-doctoral fellow at the NYU School of Medicine, in the laboratory of Dr. Heran Darwin, preparing for a career as an independent investigator. She graduated with a PhD in Parasitology in 2009 from the laboratory of Dr. Jayne Raper. Since then she has studied Mycobacterium tuberculosis (Mtb), starting with a one year post-doc working on Mtb drug discovery at the Novartis Institute for Tropical Diseases in Singapore. She joined Dr. Darwin’s laboratory in December 2010. The Darwin laboratory discovered the first ubiquitin-like modifier pathway in prokaryotes, the function of which is essential for both proteasomal degradation and pathogenesis of Mtb. Dr. Samanovic has focused her post-doctoral research on understanding the link between proteasome function and Mtb pathogenesis.

Jessica C. Seeliger, PhD

Stony Brook University

Dr. Jessica Seeliger is Assistant Professor of Pharmacological Sciences at Stony Brook University. Her research group investigates mechanisms of outer membrane biosynthesis and assembly in Mycobacterium tuberculosis. Other research areas include the development and application of tools for gene attenuation and inducible gene regulation in mycobacteria.

Smita Srivastava, PhD

NYU School of Medicine

Dr. Smita Srivastava is an Associate Research Scientist in the laboratory of Dr. Joel Ernst at the NYU School of Medicine. She did her PhD at National Institute of Immunology, India, where she identified some of the factors that contribute towards long-lived antigen specific T cell memory. Before joining Dr. Ernst’s lab at NYU, she spent some time in the laboratory of Dr. Jacek Skowronski at CSHL where her work helped identify SAMHD1, a restriction factor that defends host macrophages from HIV1 infection. The Ernst Lab has published seminal papers that have provided new insights towards understanding immune responses during M. tuberculosis infection. Dr. Srivastava’s current project involves studying the underlying mechanisms that contribute to initiation of M. tuberculosis specific adaptive immunity as well as understanding how M. tuberculosis evades immune effector mechanisms.

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Abstracts

Novel Regimens to Treat Tuberculosis — Great Hope in the Pipeline
Daniel Everitt, MD, Senior Medical Officer, Global Alliance for TB Drug Development

After a nearly 50 year hiatus in the development of any truly new drugs to treat tuberculosis (TB), bedaquiline was approved by the FDA in 2012, and bedaquiline and delamanid were approved by the EMA in 2013 for the treatment of pulmonary TB caused by multi-drug resistant (MDR) TB. While this is a great step forward, R&D is urgently needed to develop, approve and roll out simplified, affordable and safe regimens that can treat drug sensitive (DS) TB in less than the currently required 6 months and MDR TB in far less than currently required 18–30 months of treatment. The Global Alliance for TB Drug Development, a non-profit product development partnership, is currently is completing a Phase 3 trial evaluating a 4 month regimen for DS TB, is commencing a Phase 3 trial of a 4 month regimen for both DS and MDR TB, a trial of novel drugs to treat extensively drug resistant TB, and a Phase 2 trial of a regimen that may provide a 3 month therapy of patients with TB. While the clinical development of drug regimens to treat tuberculosis are challenging, there are finally new regimens that hold promise after decades with little R&D for therapeutics to address this serious disease of poverty.
 

Understanding Essentiality
Kyu Rhee, MD, PhD, Weill Cornell Medical College

Essentiality is a phenotypic trait of genes frequently used to identify new potential drug targets. However, genes function within the context of complex and extensively interconnected physiologic networks, making it difficult to discern the specific mechanisms responsible for their essentiality. Here, we report the application of a combination of chemo-genetic and metabolomic approaches to elucidate the biochemical basis of essentiality for the metabolic enzyme, isocitrate lyase (ICL), for survival on fatty acids, a major carbon source thought to be encountered in vivo.
 

Triglyceride Accumulation, Carbon Stress, and Virulence in Mycobacterium tuberculosis
Jessica C. Seeliger, PhD, Stony Brook University

Triglyceride accumulation in M. tuberculosis (Mtb) has been linked to bacterial responses to environmental stressors. Here we characterize an Mtb mutant that is severely attenuated in mice and show that the associated accumulation of intracellular triglycerides is due to a loss of lipid transport function. Growth of the mutant strain is sensitive to propionate and cholesterol carbon sources, underscoring the importance of carbon flux balance in Mtb survival.
 

Signal Transduction Across the M. tuberculosis Cell Envelope by RIP
Michael S. Glickman, MD, Memorial Sloan-Kettering Cancer Center

Mycobacterium tuberculosis must sense the host environment and respond to by altering gene expression. The Rip1 protease of M. tuberculosis is a major virulence determinant that mediates signal transduction across the M. tuberculosis cell envelope through intramembrane proteolysis of anti-Sigma factors. This lecture will present our recent insights into the coupling of Rip1 to its substrates through a substrate-specific adapter protein and the implications of this finding for M. tuberculosis signal transduction and S2P function more generally.
 

Modulation of Host Resistance to Mycobacterium tuberculosis Infection by Helminths
Padmini Salgame, PhD, Rutgers New Jersey Medical School

Researchers have long studied the impact of Mycobacterium tuberculosis infection on host immune response in the setting of a single infection and in the absence of any chronic disease. However, in the real world, M. tuberculosis-infected humans are co-infected with other bacteria, viruses and parasites or have underlying chronic disease, all of which have the potential to influence the development of host immunity against tuberculosis. Since Tuberculosis and helminthic infections coexist in many parts of the world, it is highly likely that the T helper (Th)2 and T regulatory response induced by helminths could modulate the host protective response against M. tuberculosis. The presentation will encapsulate our recent findings on the role of parasitic helminth infections in negatively modulating the course and outcome of tuberculosis disease in a murine model of coinfection.
 

Regulation of Iron Metabolism: An Essential Balancing Act Performed by Mycobacterium tuberculosis
G. Marcela Rodriguez, PhD, Rutgers New Jersey Medical School

Iron is an essential but potentially harmful nutrient, poorly soluble in aerobic conditions, and not- freely available in the human host. To obtain iron, M. tuberculosis synthesizes and secretes siderophores, small Fe3+ chelators, that sequester iron and deliver it to the bacterium, via specialized Fe3+-siderophore transporters.  Although essential, iron can also be harmful, because it readily catalyzes the generation of toxic reactive oxygen species, from normal products of aerobic respiration in the Fenton reaction. Our studies show that to set the boundaries between iron sufficiency, deficiency and toxicity Mycobacterium tuberculosis uses the iron dependent regulator IdeR as iron sensor. As a positive and negative regulator of gene expression IdeR is indispensable for M. tuberculosis adaptation to changes in iron availability. Alterations in the ability to maintain iron homeostasis render M. tuberculosis vulnerable to the stresses faced in macrophages, prevents proliferation in mice, and decreases tolerance of this pathogen to antibiotics.
 

Genetic Predisposition to Severe Tuberculosis in Children
Stephanie Boisson-Dupuis, PhD, The Rockefeller University

TB is caused by Mycobacterium tuberculosis (Mtb) and has long been considered exclusively as an infectious disease. The emergence of multi-drug resistant strains of Mtb and the association of TB with HIV result in a devastating disease with 8 million new cases per year and 2 million deaths per year. Up to one third of the world population is infected by Mtb, novel antibiotics in the pharmaceutical pipe line are scarce, and there is currently no strong candidate vaccine, raising concern that TB pandemics may worsen in the coming decades. However, only 10% of infected people develop clinical TB, including about 5% within two years after infection (known as primary tuberculosis). This form predominantly affects children, is clinically subacute and often spreads hematogenously outside the lungs. The remaining 5% of infected individuals develop TB later in life, years or decades after infection, typically due to microbial reactivation from latency, which results in the chronic pulmonary form of adult TB. Different factors, including host and microbial factors, may participate to the development of TB among infected individuals. Among them, the genetic factors of the host have been shown to play an important role in the mouse model (both by forward and reverse genetics) but also in humans (genetic epidemiological studies). Given the two distinct clinical presentations of the disease (primary vs. reactivation TB), we hypothesize that a complex, polygenic predisposition (association of polymorphisms) may be responsible for the chronic pulmonary form in adults, whereas rare monogenic variants may account for the development of severe TB in children. We will herein focus on the monogenic dissection of childhood TB, i.e. the search for single-gene inborn errors of immunity in children with severe primary TB. The investigation of a rare syndrome designated as Mendelian susceptibility to mycobacterial disease (MSMD), which is characterized by susceptibility to poorly virulent mycobacteria (BCG vaccines and environmental mycobacteria), has led to the identification of a set of 9 human genes critical for antimycobacterial immunity (IFNGR1, IFNGR2, STAT1, IRF8, CYBB, NEMO, IL12B, IL12RB1 and ISG15). The genes and their encoded proteins are all involved in IFN-γ-mediated immunity (upstream or downstream from IFN-γ), the level of IFN-γ signaling further correlating with the severity of the disease. In this context, unsurprisingly, several MSMD patients were also shown to be susceptible to TB. In addition, given the low clinical penetrance of IL-12Rβ1 deficiency for MSMD, three unrelated children with complete IL-12Rβ1 deficiency were reported to display TB but not MSMD, providing the first proof of principle that severe childhood TB may result from single-gene inborn errors of immunity. A young adult with a particularly severe form of TB was also found to carry a complete IL-12Rβ1 deficiency. The percentage of Mendelian predisposition to TB in endemic areas was further estimated by Bayesian computation to be between 5 and 45%, a percentage far from negligible. Based on these intriguing results, two candidate gene approaches were subsequently undertaken. The sequencing of the coding and flanking intron regions of IL12RB1 in a small population sample of 50 children from Morocco, Iran, and Turkey with severe TB revealed that two patients had complete IL-12Rβ1 deficiency (4%). These results strongly support the hypothesis that childhood TB may result from a collection of single-gene inborn errors of immunity, at least in a fraction of patients. However, most children with severe TB lack a genetic etiology. We now aim to identify and characterize the TB-causing genes in a population sample of children with severe TB following a genome wide approach based on whole-exome sequencing (WES) which has been pioneered in the lab for immunology and infectious diseases.
 

Proteasomal Regulation of Nitric Oxide Resistance in M. tuberculosis
Marie Samanovic, PhD, NYU Langone Medical Center

Mycobacterium tuberculosis (Mtb) resides mainly inside macrophages, which produce nitric oxide (NO) to combat mycobacterial infection. Earlier studies revealed that proteasome-associated genes are required for Mtb to resist NO via a previously uncharacterized mechanism. We performed a screen for suppressors of NO hypersensitivity in a Mycobacterium proteasomal ATPase (mpa) mutant and identified three genes.  One gene was identified twice and coded for a protein with an incorrectly annotated function. We determined that this protein is an Mtb proteasome substrate and is involved in the synthesis of a group of phytohormones called cytokinins. This new discovery elucidates the link between proteasome function, NO resistance, and virulence in Mtb.
 

Cyclic AMP (cAMP) Signaling in M. tuberculosis: Expanding the Circle
Kathleen A. McDonough, PhD, Wadsworth Center

Bacterial pathogens such as M. tuberculosis must regulate their gene expression in response to changing environments during establishment and maintenance of host infection, and this process requires communication between environmental sensors and gene regulatory factors. Cyclic AMP (cAMP) is a signal relay molecule that enables such communication, and it has central roles in the physiology of both bacterial pathogens and their mammalian hosts. The presence of ~15 distinct adenylyl cyclases provides M. tuberculosis with an unusually large capacity to generate cAMP in response to changing environments, and cAMP signaling has been shown to contribute to TB pathogenesis. This talk will focus on the differing roles of two cAMP-associated transcription factors in M. tuberculosis, Crp and Cmr. Recent experimental results, combining gene-level promoter analyses with global gene expression and in vivo transcription factor binding studies, will be discussed.
 

T cell responses to TB infection; IL-12Rb
Andrea M Cooper, PhD Trudeau Institute, Inc

Mycobacterium tuberculosis (Mtb) and humans have co-evolved over 50,000 years. During this time Mtb has become a strong initiator of human T cell responses while limiting the expression of those responses within the lung. In this presentation I will discuss the factors impacting the initiation of the acquired cellular response to Mtb. I will also discuss the factors that limit expression of this acquired response within the lung and particularly in the context of the granuloma. The critical point is that while infection is established quickly within phagocytes in the lung, the acquired response is very slow to recognize that a bacterial infection has occurred. There is no recognition of antigen by specific T cells within the lung rather the initiation of the response occurs in the draining lymph node; importantly this initiation does not occur until 7-10 days post infection. By the time specific T cells arrive back at the inflamed site within the lung, Mtb-infected phagocytes dominate the lesion and produce products which limit the ability of the T cells to survive and function. By this delaying tactic, Mtb establishes a location within the lung where it is protected from the strong immune response that it induces. Why then is the strong immune response induced?  When the acquired response is absent then the bacteria grow within the non-lung tissue and the host dies rapidly suggesting that the strong immune response is required to keep other organs relatively healthy. Thus, while the primary lesion in the lung provides a niche for bacteria to grow and disseminate to other hosts, the rest of the body is kept healthy by a strong immune response.
 

Unraveling the Tapestry of Immune Evasion by Mycobacterium tuberculosis
Steven A. Porcelli, MD, Albert Einstein College of Medicine

The coevolution of Mycobacterium tuberculosis (Mtb) with the mammalian immune system has created a delicate and complex host-pathogen relationship that is central to the success of this bacterium as a human pathogen. Our laboratory has focused mainly on understanding how mycobacteria block effective host T cell responses, and this information is being applied in studies aimed at rational design of better tuberculosis vaccines. To understand in more detail the ways in which Mtb interferes with MHC class II function in antigen presentation to CD4 T cells, we carried out gain of function genetic screens to identify Mtb genes that contribute to this aspect of immune evasion. This approach identified a member of the PE-PGRS multigene family as an important immune evasion effector. Detailed analysis of this gene indicate that it interferes with the basic cellular process of macroautophagy in Mtb infected cells, and thus limits the access of certain protein antigens to antigen processing compartments. Our results identify another thread in the tapestry of immune evasion by Mtb, and may help to generate approaches to more successful vaccination.
 

TB Treatment
Jerrold J Ellner, MD, Boston University School of Medicine

After a lapse of 4 decades, new drugs have been approved for TB treatment and are undergoing clinical trials. The end-game for new therapies is treatment shortening for drug susceptive Mycobacterium tuberculosis (Mtb) and greater activity against drug resistant TB, particularly XDR- (extensively drug resistant- and TDR (totally drug resistant isolates). For drug sensitive TB, the leading candidates for treatment shortening are the substitution of fluoroquinalones or high dose rifapentine for less active drugs. Interim studies from unpublished studies will be reviewed. Persisting organisms are the main determinant of treatment duration. The role of drug tolerance, "MIC creep," local PK, and under-dosing of rifampin will be described and a holistic model presented. In drug resistant Tb, linezolid and bedaquiline show promise. Linezolid has unprecedented activity in XDR-TB. Bedaquiline is active in MDR-TB. Unfortunately, infrequent but lethal adverse events may complicate its use. Another area of interest is immunotherapy. TB is associated with unregulated immune activation at local sites of infection. There may be an adjunctive role for "controlled" immunosuppression. Given the activity of drugs undergoing study, we will have totally different regimens in the next 5–10 years and isoniazid and ethambutol may retire to the history books.
 

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