Areas of Research

Vanderbilt University and Vanderbilt Medical Center work with local and international partners to advance the field of tuberculosis research. Specific fields of research include:

  • Reducing the human reservoir of M. tuberculosis infection through early TB detection, treatment and prevention are vital to reducing the global burden of TB.

    Active Projects:

    • TBTC Study 37, ASTEROID (Assessment of the Safety, Tolerability, and Effectiveness of Rifapentine given Daily for LTBI); Nashville, TN; PI – Timothy Sterling; CDC
    • Patient-centered intervention to prevent TB among children less than 5 years old; Peru; PI – Larissa Otero (Peru); NIH K43TW011137
    • Immune-mediated adverse drug reactions to HIV and TB treatments in South Africa: predict, prevent and improve long-term outcomes (IMARI SA study); South Africa; PIs - Elizabeth Phillips, Graeme Meintjes (South Africa); NIH R01AI152183
    • TB Treatment and Prevention at the Metro Nashville Public Health TB Clinic
    • Innovative Modelling for predicting TB treatment outcomes in global cohorts; PIs Bruno Andrade (Brazil), Timothy Sterling; CRDF Global
    • Multi-level and Intersectional Stigma and other Social determinant Effects on TB case Detection, care, and treatment outcomes: The MISSED TB Outcomes Study; PIs - Carolyn Audet; Desmond Tutu Foundation

    Completed Projects:

    • Tuberculosis Trials Consortium (TBTC); Peru; PIs – Timothy Sterling, April Pettit; CDC
    • Tuberculosis Epidemiology Studies Consortium (TBESC); Nashville, TN; PIs – April Pettit, Timothy Sterling; CDC
    • Characterizing the impact of HIV disease severity in prediction models for tuberculosis treatment outcomes; Nashville, TN; PI – Lauren Peetluk; NIH F31AI152614

  • Multidrug-resistant TB (MDR-TB), defined as resistance to at least isoniazid and rifampin, and extensively drug-resistant TB (XDR-TB), defined as MDR-TB strains that are also resistant to fluoroquinolones and second-line injectable agents, are a growing concern. Researchers at Vanderbilt, with collaborators in Tennessee as well as Cape Town and Durban, South Africa, study resistance to TB drugs, with a particular focus on the fluoroquinolones. These agents are widely used to treat other bacterial infections, which can increase the risk of drug resistance in TB, and affect the diagnosis and treatment of TB.

    Active Projects:

    • Predictors of Resistance Emergence Evaluation in MDR-TB Patients on Treatment (PRE-EMPT); India and Brazil; PIs – Robert Horsburgh (BU), Timothy Sterling; NIH R01AI134430
    • Poor Treatment Response and Outcomes in Bedaquiline-Based Treatment Regimens for Drug-Resistant Tuberculosis in South Africa; PI – Yuri van der Heijden; NIH R01AI158605
    • Drug-resistant Tuberculosis in Gauteng Province, South Africa: Understanding Facilitators and Barriers to Successful Patient Treatment; PI – Yuri van der Heijden; VUMC ID Fund
    • Mechanistic Studies of Gyrase/Topoisomerase IV-Targeted Antibacterials (R01); Nashville, TN; PI – Neil Osheroff; NIH R01AI170546
    • Mechanistic Studies of Type II Topoisomerases and Topoisomerase-Targeted Agents (R01); Nashville, TN; PI – Neil Osheroff; NIH R01GM126363
    • Fluoroquinolones and Efflux-Mediated Cross Resistance in HIV-related TB; Nashville, TN; PI – Timothy Sterling
    • Mechanisms of antibiotic resistance development in bacterial pathogens; Nashville, TN; PI - Houra Merrikh; NIH R01AI127422

    Completed Projects:

    • Fluoroquinolone resistance in patients with multidrug-resistant tuberculosis; South Africa; PI – Yuri van der Heijden; NIH K08AI106420
    • Mechanisms of Quinolone Resistance; Nashville, TN; PI – Neil Osheroff; VA Grant

  • TB is closely linked to HIV; HIV has been a key contributor to the TB epidemic. People with living with M. tuberculosis and HIV infection are significantly more likely to develop TB than people who are HIV-negative. To control TB in high HIV-prevalence settings, it is imperative to coordinate efforts for TB and HIV control. Vanderbilt collaborates with international organizations and performs studies in population-based cohorts to identify ways to reduce the burden of TB among people living with HIV. 

    Active Projects:

    • International Epidemiologic Databases to Evaluate AIDS (IeDEA), NIH
      • Caribbean, Central, and South America network for HIV Epidemiology (CCASAnet); Argentina, Brazil, Chile, Haiti, Honduras, Mexico, Peru; PIs – Jessica Castilho, Stephany Duda, Pedro Cahn (Argentina); NIH U01AI069923
      • The North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); Nashville, TN; PIs – Richard Moore (JHU), Keri Althoff (JHU), Timothy Sterling (VUMC Site PI); NIH U01AI069918
    • Regional Prospective Observational Research for Tuberculosis (RePORT)- South Africa; PIs – Mark Hatherill (South Africa), Timothy Sterling; CRDF Global
    • Regional Prospective Observational Research for Tuberculosis (RePORT)- Philippines; TB Pathogenomics Study - PI - Ribka Berhanu; CRDF Global
    • Associative BRICS Research in COVID-19 and Tuberculosis (ABRICOT); PIs - Valeria Rolla (Brazil), Timothy Sterling (VUMC); CRDF Global
    • Avante: Towards Epidemic Control, improving TB/HIV diagnosis and care in Mozambique; PI – Bill Wester; CDC/PEPFAR
    • AIDS Clinical Trials Group (ACTG) for Research on Therapeutics for HIV and Related Infections [TSG TB] (UM1); PIs- Judith Currier (UCLA) Kelly Dooley (VUMC); NIH UM1AI068636
    • Statistical methods for correlated outcome and covariate errors in studies of HIV/AIDS; South America and East Africa; PI – Bryan Shepherd; NIH R01AI131771
    • The Antiretroviral Therapy Cohort Collaboration (ART-CC); North America and Europe; PI – Jonathan Sterne, Timothy Sterling; NIH U01AA026209
    • Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens (R01); PIs - Joel Ernst (UCSF) Timothy Sterling; NIH R01AI173002

    Completed Projects:

    • Immune activation and dysglycemia in tuberculosis patients with and without HIV; South Africa; PIs – Yuri van der Heijden, John Koethe, Al Leslie (South Africa); CRDF Global
    • Predictors of treatment toxicity, failure, and relapse in HIV-related tuberculosis; Brazil; PIs – Timothy Sterling, Valeria Rolla (Brazil); NIH R01AI120790

  • Understanding how TB develops in the body is key to developing novel approaches to combating this disease. Researchers at Vanderbilt along with international collaborators have been working on improving our understanding of the mechanisms behind M. tuberculosis transmission and pathogenesis.

    Active Projects:

    • Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil; PIs – Timothy Sterling, Bruno Andrade (Brazil); NIH U01AI069923
    • RePORT International Coordinating Center (RICC) 3.0; PIs – Jerrod Ellner (Rutgers), Timothy Sterling; CRDF Global
    • Epidemiologic, immunologic, and genetic predictors and mechanisms of incipient, sub-clinical, and active TB in HIV-infected and -uninfected close TB contacts; Brazil; PIs – Timothy Sterling, Bruno Andrade (Brazil), Thomas Hawn (UW); NIH R01AI147765
    • Characterization of Genomics and Metabolomics among Individuals Highly-Exposed, but resistant to Mtb Infection; PIs - Neel Gandhi (Emory); NIH R01AI139406
    • Prevalence, Incidence, and Biomarkers of Subclinical Tuberculosis (TB) in Close Contacts in the RePORT International Consortium; Brazil; PI - Timothy Sterling; CRDF Global

    Completed Projects:

    • Molecular analysis of the adaptive immune response to tuberculosis; Nashville, TN; PI – Spyros Kalams; NIH R21AI127129
    • Towards a global TB biomarker: Comparison of small transcriptomic signatures to predict, diagnose and monitor TB disease; Brazil, South Africa; PIs – Bruno Andrade (Brazil), Timothy Sterling, Mbandi Kimbung; CRDF Global
    • Prospective profiling of eicosanoid and inflammatory balance in TB-diabetes; Brazil; PIs – Timothy Sterling, Bruno Andrade (Brazil), John Koethe, Henrique Serezani; CRDF Global
    • RePORT International Coordinating Center (RICC); PIs – Jerrod Ellner (Rutgers), Timothy Sterling; CRDF Global
    • Tuberculosis Epidemiologic Studies; PIs - April Pettit, Tim Sterling; CDC 
    • Registry Linkage to Improve Mortality Ascertainment and Assessment of Engagement in Care in Brazil, Mexico, and Peru; PIs - Peter Rebeiro, Stephany Duda; NIH R21AI145686

    • Macrophage immunogenetics and incipient tuberculosis in Brazil; Brazil; PIs – Thomas Hawn (UW), Timothy Sterling, Bruno Andrade (Brazil); CRDF Global

       

    TB-macrophage host-pathogen interactions
    The question of why some tuberculosis patients develop acute/severe disease while most do not remains one of the most pressing in the field. We know that the onset and progression of tuberculosis are greatly influenced by the initial interaction between Mtb and its host cell, the macrophage. Using a combination of in vitro, ex vivo, and mouse models, Vanderbilt researchers are working to identify molecular “tipping points” that skew the Mtb-macrophage host pathogen interface, with the goal of developing host-directed therapeutics that combat infection and protect TB patients from harmful immunopathology.

    • Targeting mediators of oxidative stress to limit hyperinflammatory cell death modalities during Mycobacterium tuberculosis infection; PIs - Watson, Patrick; NIH R01AI179037-01A1
    • Mitochondria as crucial regulators of innate immune outcomes during Mycobacterium tuberculosis infection; PIs - Watson, Patrick; NIH R01AI155621  

  • Rapid and accurate diagnosis is critical for timely initiation of TB treatment, but many people with TB (or TB symptoms) do not have access to adequate initial diagnosis. New tools and diagnostics are needed that can accurately diagnosis TB disease and be utilized in settings across the globe.

    Active Projects:

    • A 100-fold more sensitive TB diagnostic based on magnetic concentration and "coffee ring" formation; PIs – David Wright and Rick Haselton; NIH R01AI135937
    • Novel urine lipoarabinomannan (LAM) test; Brazil; PIs - David Wright, Micaella Jorge, Valeria Rolla, Adriano Gomes
    • Sputum PCR-based test (Truenat) for the diagnosis of TB; Brazil; PIs – Afranio Kritski (Brazil)
    • Urine TB diagnostic by amplicon reconstruction for PCR detection of DNA fragments; PI – Rick Haselton; NIH R21AI152497
    • Harmonist: A Scalable Toolkit for Standardizing and Coordinating Data Sharing Across International Research Networks (R24); PI - Stephany Duda; NIH R24AI124872

    Completed Projects:

    • RePORT International Data Harmonization; PIs - Timothy Sterling, Stephany Duda; CRDF Global
    • Urine TB diagnostic by amplicon reconstruction for PCR detection of DNA fragments; PI – Rick Haselton; NIH R21AI152497

  • Improving existing treatment and therapy options by utilizing expertise in the pharmacology of anti-TB drugs; through the use of pharmacokinetic/pharmacodynamic (PK/PD) analysis to optimize treatment regimens; and the exploration of safety and PK in people living with HIV, children and pregnant women.

    Active Projects:

    • Second Generation InSTIs for the Treatment of HIV-1 in patients with TB co-infection on Rifampicin-based Treatment in KwaZulu Natal, South Africa; South Africa; PIs - Naidoo, Anushka, Kelly Dooley; NIH R01AI152142
    • Preclinical Design and Clinical Translation of TB Regimens (PReDicTR) Consortium (UM1); PIs - Rada Savic (UCSF) Kelly Dooley (VUMC); NIH UM1AI179699
    • Investigating Multiple PK and PD Relationships for TB-HIV (IMPPRove TB-HIV) (R56); PI - Kelly Dooley; NIH R56AI174911
    • Baseline pRescription According to Direct from Sputum Sequencing and TArgeted drug Concentration Strategy (BRASS TACS) (R01); PI - Jeffery Tornheim (Johns Hopkins) Kelly Dooley (VUMC); NIH R01AI168371
    • ACTG Study A5409, "A Phase 2A+ Randomized, Adaptive, Dose-Ranging, Open-Label Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis (RAD-TB)"

    Completed Projects

    • Innovative PK/PD approaches to optimize TBM treatment in children (TBM-KIDS trial); Baltimore, MD; PI - Kelly Dooley; NIH R01HD074944
    • Phase 2 Study of PA-824 for Treatment of Pulmonary Tuberculosis IND 117472; Baltimore, MD; PI - Kelly Dooley; FDA R01FD004794
    • Ph2a Study: Rifampin, Meropenem, Augmentin for Tuberculosis (COMRADE trial) IND 129159; Baltimore, MD; PI - Kelly Dooley; FDA R01FD005724

  • Improving existing treatment and therapy options for Nontuberculous Mycobacteria is of critical importance. The VTC is working to advance knowledge, diagnosis, and treatment of NTM. 
     

    Active Projects:

    • A Phase 2/3, Randomized, Double-blind, Placebo-controlled, Multicenter, Prospective Study to Assess the Efficacy, Safety, and Pharmacokinetics of Orally Administered Epetraborole in Patients with Treatment-refractory Mycobacterium avium Complex Lung Disease (MACrO2); PI - Christina Fiske; Medpace Clinical Research LLC
    • A Phase 2, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Omadacycline in Adult Subjects with Nontuberculous Mycobacterial (NTM) Pulmonary Disease Caused by Mycobacterium abscessus Complex (MABc); PI - Kelly Dooley; Paratek Phamaceuticals, Inc.
       

  • The VTC aims to train the next generation of TB scientists, enabling them to succeed in their research and academic goals, and provide opportunities for TB training.

    Active Projects:

    • HIV-Associated Tuberculosis Training Program (HATTP); South Africa; PIs – Graeme Meintjes (South Africa), David Haas; NIH D43TW010559 
    • RePORT Advanced Career Training Program (ReACT); Brazil; PIs - Timothy Sterling, Bruno Andrade (Brazil); NIH U01AI069923
    • Mentoring Investigators in HIV and Tuberculosis Therapeutics Research; Nashville, TN; PI – Kelly Dooley; NIH K24AI150349
    • Vanderbilt SCHolars in HIV and Heart, Lung, Blood, and Sleep ReSearch (V-SCHoLARS); Nashville, TN; PIs – Matthew Freiberg, John Koethe; NIH K12HL143956
    • Vanderbilt Infection Pathogenesis and Epidemiology Research Training Program (VIPER); Nashville, TN; PIs – Spyros Kalams; NIH T32AI007474
    • Centers for AIDS Research (CFAR); Nashville, TN; PIs – Simon Mallal, David Haas; NIH P30AI110527