Overview
Pathogenesis of Tuberculosis
Approximately eight million people develop active tuberculosis (TB) each year with two million dying from the disease. In addition, it is estimated that one third of the world’s population is chronically infected with Mycobacterium tuberculosis (Mtb). Most individuals respond to infection with Mtb by mounting a strong cellular immune response that prevents active disease but does not sterilize the infection. Mtb has developed strategies to persist within macrophages, its major host cells, even in the face of fully developed T cell immunity. Thus, there is a fine balance between the host immune response that controls infection and the pathogen’s ability to evade and manipulate this response.
To better understand the molecular basis for Mtb’s ability to resist host defense mechanisms we characterize Mtb mutants that are susceptible to stresses encountered by the bacterium during persistence within the host. In an infected host, Mtb primarily resides within the phagosomes of macrophages and is able to arrest phagosome maturation. However, after cytokine activation of the macrophage, the phagosome matures along the endosomal-lysosomal pathway. Mtb persists within mature phagosomes, indicating that the bacterium possesses resistance mechanisms against defenses of activated macrophages, such as low pH, nitric oxide and others. We have identified Mtb mutants that are hyper susceptible to such stress conditions. Some of these mutants are also attenuated in the mouse model of TB. The identification and characterization of the molecular mechanisms underlying the loss of stress resistance and loss of virulence of these mutants will help better understand the intracellular environment encountered by Mtb and how the pathogen resists host defense mechanisms.
We are also interested in the metabolic environment Mtb faces within its host. Metabolic adaptation to the host niche is a defining feature of the pathogenicity of Mtb, yet Mtb’s central carbon metabolism remains remain incompletely defined. We are investigating the metabolic pathways Mtb requires to establish and maintain chronic infections.
In collaboration with Dr. Schnappinger’s laboratory (Department of Microbiology, Weill Medical College of Cornell University) we developed controlled expression systems that allow silencing of mycobacterial genes in vitro and in vivo. We apply these systems to create conditional knock-downs of mycobacterial genes that are important for growth and persistence within the host. These conditional knock-downs allow us to investigate if a mycobacterial gene is required at all or only at specific stages of an infection. They also are also used for drug target evaluation and studies of essential mycobacterial genes.
Keywords:
infectious disease, tuberculosis, macrophage, host response, carbon metabolism
Email address:sae2004@med.cornell.edu
Highlights
- 1Proceedings of the National Academy of Sciences of the United States of America · 2021
- 2
- 3Nature communications · 2021
Publications
Funding
Active
17 grants- MPIP01AI202868-06Determinants of TB Control, Relapse, and ReinfectionNational Institute of Allergy and Infectious Diseases · 2026–2031
- Co-IP01AI181935-01A1Microbiology of Treatment Shortening in TuberculosisNational Institute of Allergy and Infectious Diseases · 2026–2031
- PIP01AI143575-06Mechanisms and Consequences of Clinical Pressure on Pathways in MtbNational Institute of Allergy and Infectious Diseases · 2020–2031· 2 renewals
- KPINV-100452TB gene modulation to build shorter drug regimensBill & Melinda Gates Foundation · 2026–2029
- MPIR01AI192524-01Understanding resistance and tolerance to nitroimidazoles in Mycobacterium tuberculosisNational Institute of Allergy and Infectious Diseases · 2025–2029
- Sub-PIR01AI184469-03Molecular basis of antibiotic resilience in Mycobacterium tuberculosisNational Institute of Allergy and Infectious Diseases · 2024–2029 · via Harvard University
- Co-IUM1AI179699-01Preclinical Design and Clinical Translation of TB Regimens (PReDicTR) ConsortiumNational Institute of Allergy and Infectious Diseases · 2024–2029 · via University of California, San Francisco
- Sub-PIWC-206057-206058Pulmonary TB-CHIM ProgrammeWellcome Trust · 2025–2028 · via Harvard University
- MPIR01AI177560-04M. tuberculosis carbon metabolism during infectionNational Institute of Allergy and Infectious Diseases · 2023–2028
- MPIR21AI190768-01A1Conditional M. tuberculosis knockdown mutants in mice with human-like pathologyNational Institute of Allergy and Infectious Diseases · 2026–2028
- MPIP30AI168433-05Tri-Institutional Tuberculosis Research Advancement CenterNational Institute of Allergy and Infectious Diseases · 2022–2027
- Co-IK08AI148584-01A1The Transmission Biology of Mycobacterium TuberculosisNational Institute of Allergy and Infectious Diseases · 2021–2027Career
- Co-IBMGF INV-055894Gene inactivation and modulation of Mtb targets to build combinationsBill & Melinda Gates Foundation · 2023–2026
- Co-IBMGF INV-055896Conditional Mtb knockdown mutants for TB drug discoveryBill & Melinda Gates Foundation · 2023–2026
- Sub-PIR01AI161013-05Harnessing B Cells For TB Vaccine Development To Improve Therapy Of TB And TB-HIV CoinfectionNational Institute of Allergy and Infectious Diseases · 2021–2026 · via Center for Discovery and Innovation
- Co-IBI 230987-03Chemical Genomics of TuberculosisBill & Melinda Gates Foundation · 2022–2026 · via Broad Institute Inc
- PIU19AI162568-05S1Determinants of TB control, relapse and reinfection - Foreign Funding SupplementNational Institute of Allergy and Infectious Diseases · 2021–2026· 2 renewals
Completed grants (26)
- Co-IBI 240369-01Development of a comprehensive RNAseq database of hypomorphs for small molecule target Identification against Mycobacterium tuberculosisBill & Melinda Gates Foundation · 2023–2025 · via Broad Institute Inc
- KPPMF 231585-01Characterization of a mycobacterial determinant of intrinsic multidrug resistancePotts Memorial Foundation · 2023–2025
- Co-IR21AI168673-02Determination of the mode of action of the antibiotic pyrazinamideNational Institute of Allergy and Infectious Diseases · 2022–2025
- PIR21AI168506-02Turning Mycobacterium tuberculosis appetite for fatty acids against itselfNational Institute of Allergy and Infectious Diseases · 2022–2025
- KPF31AI169872-01A1Investigating genetic regulators of Mycobacterium tuberculosis cell division and their role in persistent tuberculosis infectionNational Institute of Allergy and Infectious Diseases · 2022–2024Fellowship
- KPPMF 222011-01Studying the role of macrophages and gluconeogenesis in the regulation of Mycobacterium tuberculosis persistence in a mouse model of latencyPotts Memorial Foundation · 2021–2024
- PI5 R01 AI063446=15Conditional Expression of Mycobacterial GenesNational Institute of Allergy and Infectious Diseases · 2018–2024
- PIR01AI135629-05Conditionally Replicating Mycobacterium Tuberculosis VaccinesNational Institute of Allergy and Infectious Diseases · 2018–2024
- KPF30HL151085-01A1Ironing out mycobacterial persistence: Iron access and utilization in chronic mycobacterial infectionNational Heart, Lung, and Blood Institute · 2020–2024
- MPIR01AI143788-05Development of a self inactivating, highly effective TB vaccineNational Institute of Allergy and Infectious Diseases · 2019–2024 · via University of Pittsburgh
- PIT32AI134632-05Immunology and Microbial Pathogenesis Research Training ProgramNational Institute of Allergy and Infectious Diseases · 2019–2024Training
- Co-IBMGF 210849-01Conditional M. tuberculosis knockdown mutants for TB drug discovery (INV-004761)Bill & Melinda Gates Foundation · 2020–2023
- KPNSF 1746886Defining Mycobacterium tuberculosis as a lung pathobiontNational Science Foundation · 2020–2023Fellowship
- Sub-PIW81XWH-17-PRMRP-FPAChemigenomic Drug Discovery for TuberculosisU.S. Department of Defense · 2017–2022 · via Harvard University
- Co-IOPP 1207840Chemical Genomics of TuberculosisBill & Melinda Gates Foundation · 2018–2022 · via Broad Institute Inc
- Co-IBMGF INV-009731Vulnerability of M. Tuberculosis to Partial Gene InactivationBill & Melinda Gates Foundation · 2017–2021
- KPU19AI111143-05Tri-Institutional TB Research Unit: Persistence and LatencyNational Institute of Allergy and Infectious Diseases · 2014–2021· 2 renewals
- Co-IBMGF OPP1024065Conditional M. Tuberculosis Knockdown Mutants for TB Drug DevelopmentBill & Melinda Gates Foundation · 2017–2020
- Co-IHHSN2612015000031Conditionally Replicating Strains of BCGNational Cancer Institute · 2018–2019 · via Harvard T. H. Chan School of Public Health
- Co-IU19AI107774-05Decoding the Roles of Critical Genes of Unknown Function in M. tuberculosisNational Institute of Allergy and Infectious Diseases · 2013–2019 · via Harvard University
- KPOPP1024065Conditional M. Tuberculosis Knockdown Mutants for TB Drug DevelopmentBill & Melinda Gates Foundation · 2010–2018
- KPOPP1084233Comprehensive Chemigenomic Approach to Tuberculosis (CCAT)Bill & Melinda Gates Foundation · 2014–2018 · via Broad Institute Inc
- PIR01AI063446-09Conditional Expression of Mycobacterial GenesNational Institute of Allergy and Infectious Diseases · 2012–2018
- PIR01AI092573-05 EWDrug Targets in Mtb GluconeogenesisNational Institute of Allergy and Infectious Diseases · 2010–2016
- PIR01AI081725-05pH Homeostasis in Mycobacterium TuberculosisNational Institute of Allergy and Infectious Diseases · 2009–2014
- PIR01HL068525-05Macrophage Gene Expression: Impact of M. tuberculosisNHLBI · 2001–2007 · via NIH RePORTER
News mentions
- Dr. Sabine Ehrt Named Chair of the Department of Microbiology and Immunology at Weill Cornell MedicineApril 14, 2025
As chair, Dr. Ehrt seeks to build on the department’s already robust national and international footprint in tuberculosis research and expand its portfolio in other areas of research and innovation.
- Designing Self-Destructing Bacteria to Make Effective Tuberculosis VaccinesFebruary 25, 2025
Working toward more effective tuberculosis (TB) vaccines, researchers have developed two strains of mycobacteria with "kill switches" that can be triggered to stop the bacteria after they activate an immune response.
- Weill Cornell Medicine Receives Grants for Tuberculosis Drug DevelopmentDecember 21, 2023
Weill Cornell Medicine researchers and the TB Drug Accelerator have received two grants totaling $6.8 million from the Bill & Melinda Gates Foundation to study tuberculosis (TB) drug development.
- $5 Million NIH Center Grant Will Support Next Generation TB ResearchSeptember 7, 2022
Weill Cornell Medicine has been awarded a five-year, $5 million grant from the National Institutes of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health to establish a new multi-institutional center for tuberculosis (TB) research and training the next generation of TB investigators.
- CinA Protein Contributes to Drug Tolerance in Mycobacterium tuberculosisMay 4, 2022
Weill Cornell Medicine researchers have identified a protein in Mycobacterium tuberculosis (Mtb) that contributes to drug tolerance, a phenomenon that allows bacteria to survive treatment with drugs that would normally kill them.
Show 3 more mentions
- Researchers Identify a Promising New Target for Tuberculosis TreatmentDecember 21, 2021
Mycobacterium tuberculosis (Mtb), the hardy bacterial species that causes tuberculosis (TB), has an unexpected vulnerability that future drugs may be able to exploit.
- Weill Cornell Advances TB Research with Support from NIHSeptember 3, 2021
Tuberculosis (TB) is a wily old killer, one of the deadliest infectious diseases in history and one of the few that naturally infects only humans.
- Graduate Students Honored in Virtual Convocation CeremonyMay 27, 2020
The Weill Cornell Graduate School of Medical Sciences honored the Class of 2020 for their academic achievements during a virtual convocation ceremony on May 27. Students and their families and friends watched a livestream of the event, as graduate school faculty announced the recipients of special awards and prizes.
Mentoring
- TKThais KlevornImmunology & Microbial Pathogenesis (PhD) · Class of 2025
- RWRuojun WangImmunology & Microbial Pathogenesis · Class of 2019
- SPSusan PuckettImmunology & Microbial Pathogenesis (PhD) · Class of 2015
- WXWeizhen XuImmunology & Microbial Pathogenesis (PhD) · Class of 2017
- FMFrances MarksMolecular Biology (PhD) · Class of 2025
- MWMeredith WhitakerImmunology & Microbial Pathogenesis (PhD) · Class of 2020
- RMRuoyao MaPostdoc mentee · 2022–2025
- YLYao LiuPostdoc mentee · 2021–2022
- UGUday GanapathyImmunology & Microbial Pathogenesis (PhD) · Class of 2015
External relationships
Advisory/Scientific Board Member
Heiser Program for Research in Leprosy & Tuberculosis · TB Alliance