Case Western Reserve University Tuberculosis Research Unit
  Integrating research to combat the global TB epidemic

Major Scientific Insights that Impact New Approaches to TB Treatment and Prevention

  1. Adjuvant immune therapy during TB treatment for drug sensitive TB: it is difficult to demonstrate a benefit (M. vaccae, rIL-2 trials) when 2 month culture conversion on solid media is the endpoint.
  2. EBA studies evaluated the following existing antibiotics: moxifloxacin, high dose levofloxacin, gatifloxacin, linezolid and found them to be effective TB drugs.
  3. EBA studies are much improved when combined with PK/PD studies; TBRU was one of the first to use them systematically with EBA studies and this has become the new standard for EBA studies worldwide.
  4. BCG vaccination of HIV exposed (but not infected) infants induces effective immune responses and has resulted in a new WHO recommendation to not vaccinate infants with BCG when they are known to be HIV infected.
  5. The combination of rapid sterilization of sputum (negative 2 mo. sputum culture) and absence of cavities on CXR fail to identify persons who can be treated with a shortened course (4 vs 6 months) with current anti-TB drugs.  Thus better biomarkers than combining the two most commonly used to assess severity of TB disease are needed to identify persons who could benefit from shortened TB treatment with current or new anti-TB drugs.
  6. Differences in growth of M. tuberculosis in human mononuclear phagocytes correlates with epidemiological data suggesting differences in M. tuberculosis strain virulence (i.e. households with minimal infection/disease vs. those with more infection/disease).
  7. Sputum cytokines (IFN-gamma, TNF-alpha) can be detected in TB patients and correlate with changes in sputum CFU over time, and thus may represent a promising host biomarker of response to treatment.
  8. CD8+ T cell responses to M. tuberculosis proteins are characterized by marked diversity in range of antigens recognized and differ from those of CD4+ T cells, indicating an urgent need for further characterize the human CD4 and CD8 T cell repertoire to M. tuberculosis protein antigens to identify optimal and dominant antigens for vaccine and diagnostic development.
  9. Human genetics influence not only progression of M. tuberculosis infection from LTBI to TB, but also whether one becomes infected and risk for progression when HIV co-infected.
  10. TNF-alpha and IFN-gamma responses to M. tuberculosis proteins are in part determined by host genetics.
  11. Baseline immune responses in household contacts can be used to predict those who will become M. tuberculosis infected (i.e. become a TST converter) and thus at higher risk for progression from infection to disease.
  12. mRNA of M. tuberculosis genes can be detected in sputum and thus a possible microbial biomarker of response to TB treatment.
  13. Inhibiting immune activation with corticosteroids during TB treatment in HIV-infected persons does not provide long-term benefit in terms of HIV progression or improved responses to TB treatment.
  14. HIV-infection and active TB are synergistic, resulting in each disease worsening the other.