Variation in M. tuberculosis in response to host selection

Summary

Principal Investigator: Sarah Fortune
Abstract: 07-ABSTRACT All pathogens that cause chronic infections must avoid clearance by the host immune response. Many have complex mechanisms to rapidly generate diversity in critical antigens. Mycobacterium tuberculosis chronically infects one third of the worlds'population and similarly must avoid clearance by the host immune system. However, there is currently little understanding of whether M. tuberculosis, like so many other pathogens, diversifies in vivo to escape host immune selection. In this proposal, we will test the hypothesis that M. tuberculosis varies, either genetically or epigenetically, during the course of infection and that this variation contributes to the ability of the bacteria to avoid clearance by the host immune response. We will use new genomics technologies[unreadable]low cost genome sequencing and expression profiling[unreadable]to systematically assess genetic and epigenetic variation in bacteria selected in a simple experimental model of disease chosen to create different immune pressures on the bacteria [unreadable]mice of different MHC haplotypes. In these studies, we expect to provide fundamental insights into the mechanisms and targets of diversifying immune selection in M. tuberculosis.
Funding Period: 2007-09-30 - 2012-08-31
more information: NIH RePORT

Top Publications

  1. pmc Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing
    Philana Ling Lin
    1 Department of Pediatrics, Children s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA 2
    Nat Med 20:75-9. 2014
  2. ncbi Persisters and beyond: mechanisms of phenotypic drug resistance and drug tolerance in bacteria
    Jemila C Kester
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
    Crit Rev Biochem Mol Biol 49:91-101. 2014
  3. pmc DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis
    Scarlet S Shell
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America
    PLoS Pathog 9:e1003419. 2013
  4. pmc Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis
    Christopher B Ford
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
    Nat Genet 45:784-90. 2013
  5. pmc Magnetic barcode assay for genetic detection of pathogens
    Monty Liong
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Nat Commun 4:1752. 2013
  6. pmc The mutation rate of mycobacterial repetitive unit loci in strains of M. tuberculosis from cynomolgus macaque infection
    Mark N Ragheb
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
    BMC Genomics 14:145. 2013
  7. pmc Efferocytosis is an innate antibacterial mechanism
    Constance J Martin
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Cell Host Microbe 12:289-300. 2012
  8. pmc Mycobacterium tuberculosis--heterogeneity revealed through whole genome sequencing
    Chris Ford
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, 665 Huntington Avenue, Building 1, Boston, MA 02115, USA
    Tuberculosis (Edinb) 92:194-201. 2012
  9. pmc Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection
    Christopher B Ford
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA
    Nat Genet 43:482-6. 2011

Detail Information

Publications10

  1. pmc Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing
    Philana Ling Lin
    1 Department of Pediatrics, Children s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA 2
    Nat Med 20:75-9. 2014
    ..Defining the local factors that dictate outcome will be useful in developing effective interventions to prevent active TB. ..
  2. ncbi Persisters and beyond: mechanisms of phenotypic drug resistance and drug tolerance in bacteria
    Jemila C Kester
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
    Crit Rev Biochem Mol Biol 49:91-101. 2014
    ..Here we review mechanisms of phenotypic drug tolerance and resistance in bacteria with the goal of providing a framework for understanding the similarities and differences in these cells...
  3. pmc DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis
    Scarlet S Shell
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America
    PLoS Pathog 9:e1003419. 2013
    ..Our results indicate that MamA influences gene expression in M. tuberculosis and plays an important but strain-specific role in fitness during hypoxia...
  4. pmc Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis
    Christopher B Ford
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
    Nat Genet 45:784-90. 2013
    ..These data suggest that interventions to prevent the emergence of drug-resistant tuberculosis should target bacterial as well as treatment-related risk factors. ..
  5. pmc Magnetic barcode assay for genetic detection of pathogens
    Monty Liong
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Nat Commun 4:1752. 2013
    ..tuberculosis-positive patient specimens. Combined with portable systems, the magnetic barcode assay holds promise to become a sensitive, high-throughput and low-cost platform for point-of-care diagnostics...
  6. pmc The mutation rate of mycobacterial repetitive unit loci in strains of M. tuberculosis from cynomolgus macaque infection
    Mark N Ragheb
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
    BMC Genomics 14:145. 2013
    ..From these data, we have estimated the rate of MIRU variation in the host environment, providing a benchmark rate for future epidemiologic work...
  7. pmc Efferocytosis is an innate antibacterial mechanism
    Constance J Martin
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Cell Host Microbe 12:289-300. 2012
    ..While efferocytosis is recognized as a constitutive housekeeping function of macrophages, these data indicate that it can also function as an antimicrobial effector mechanism...
  8. pmc Mycobacterium tuberculosis--heterogeneity revealed through whole genome sequencing
    Chris Ford
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, 665 Huntington Avenue, Building 1, Boston, MA 02115, USA
    Tuberculosis (Edinb) 92:194-201. 2012
    ..Finally, we discuss the current WGS approaches, their strengths and limitations...
  9. pmc Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection
    Christopher B Ford
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA
    Nat Genet 43:482-6. 2011
    ..We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance...