Mycobacterium tuberculosis Comparative Database

Mycobacterium tuberculosis F11 (finished)

Mycobacterium tuberculosis causes 8-9 million cases of infection, and 1.5 million deaths every year. These numbers are on the rise globally, especially in Africa, Eastern Europe and the former Soviet Union. Part of the problem in treating TB is the appearance of drug resistant TB strains, including strains with multiple drug resistance (MDR) and, more recently, strains with extensive drug resistance (XDR), which are much more difficult to treat.

In this project, we are performing sequencing and comparative analysis of multiple patient isolates with varying clinical phenotypes and disease epidemiology. Our goal is to have a better understanding of the molecular basis of fundamental clinical phenotypes such as TB transmission and drug resistance.

Project Information

We are sequencing 8 strains of Mycobacterium tuberculosis towards the ends of better understanding, treating, and ultimately eradicating this deadly human pathogen. The genome sequences of several strains of M. tuberculosis and several related Mycobacterium species have provided valuable insights into the biology of this organism (1-4). This project is focused on understanding the molecular basis of fundamental clinical phenotypes such as TB transmission and multidrug-resistance. Hence we will perform sequencing and comparative analysis of patient isolates with the most important clinical phenotypes and disease epidemiology: varied degree of spread, drug resistance, and clinical severity.

Collaborators for this project include:

  • Dr. Megan Murray, Harvard School of Public Health, USA
  • Dr. Eric Rubin, Harvard Medical School, USA

Questions about the project should be directed to annotation-webmaster@broad.mit.edu.

What is Mycobacterium tuberculosis?

M. tuberculosis is a gram-positive bacterium which causes tuberculosis, the leading cause of infectious disease mortality. About 1.5 million people die from tuberculosis each year, and it is thought that as many as 2 billion people (one third of the human population of Earth) may be infected with M. tuberculosis (5). There are about 8-9 million new cases of TB annually, with much of the burden falling on the young and middle aged between 15-49 years old (6).

Historically, tuberculosis has probably killed more than 100 million people in the past 100 years despite the fact that treatment for most forms of the disease has been available for over 50 years. Although there has been a decline in tuberculosis incidence in some areas of Western Europe and the Americas, incidence has increased dramatically in Africa, Eastern Europe and the former Soviet Union so that overall, the global caseload continues to rise (11). The concurrent HIV/TB interactions explain much of the rise in burden in sub-Saharan Africa, and the emergence of specific epidemic strains that may be especially successful pathogens may have contributed to the upward trends in incidence in some areas (12,13).

Drug resistant tuberculosis is a significant and growing public health threat. A recent report on the Global Project on anti-tuberculosis drug resistance surveillance found a median prevalence of resistance to at least one anti-tuberculosis drug of 10.2% while multidrug-resistant (MDR) TB prevalence reached as high as 14.2%. Since most cases of tuberculosis infection result in latent infection, it is estimated that there may be as many as 50 million people now infected with drug resistant tuberculosis (7, 8).

Drug resistance has made treatment of TB much more difficult. Therapy requires the use of second-line drugs which have a greater risk of adverse effects and lower potency than first-line drugs (9). The additional costs of drug-sensitivity testing, second-line drugs and the additional medical care required to administer them are exorbitant; it is estimated that the cost of treating a patient carrying MDR strains is hundreds of times greater than that for patients carrying drug sensitive strains (10).

References

  1. Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR, Honore N, Garnier T, Churcher C, Harris D, Mungall K, Basham D, Brown D, Chillingworth T, Connor R, Davies RM, Devlin K, Duthoy S, Feltwell T, Fraser A, Hamlin N, Holroyd S, Hornsby T, Jagels K, Lacroix C, Maclean J, Moule S, Murphy L, Oliver K, Quail MA, Rajandream MA, Rutherford KM, Rutter S, Seeger K, Simon S, Simmonds M, Skelton J, Squares R, Squares S, Stevens K, Taylor K, Whitehead S, Woodward JR, Barrell BG. Massive gene decay in the leprosy bacillus. Nature. 2001 Feb 22;409(6823):1007-11.
  2. Garnier T, Eiglmeier K, Camus JC, Medina N, Mansoor H, Pryor M, Duthoy S, Grondin S, Lacroix C, Monsempe C, Simon S, Harris B, Atkin R, Doggett J, Mayes R, Keating L, Wheeler PR, Parkhill J, Barrell BG, Cole ST, Gordon SV, Hewinson RG. The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7877-82.
  3. Fleischmann RD, Alland D, Eisen JA, Carpenter L, White O, Peterson J, DeBoy R, Dodson R, Gwinn M, Haft D, Hickey E, Kolonay JF, Nelson WC, Umayam LA, Ermolaeva M, Salzberg SL, Delcher A, Utterback T, Weidman J, Khouri H, Gill J, Mikula A, Bishai W, Jacobs Jr WR Jr, Venter JC, Fraser CM. Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J Bacteriol. 2002 Oct;184(19):5479-90.
  4. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE 3rd, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998 Jun 11;393(6685):537-44.
  5. Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet. 2003;362(9387):887-99.
  6. Cegielski JP, Chin DP, Espinal MA, Frieden TR, Rodriquez Cruz R, Talbot EA,Weil DE, Zaleskis R, Raviglione MC. The global tuberculosis situation. Progress and problems in the 20th century, prospects for the 21st century. Infect Dis Clin North Am. 2002;16(1):1-58.
  7. World Health Organization website on multi-drug resistance and TB.
  8. Hatfull GF, Jacobs WR Jr, editors. Molecular genetics of mycobacteria. Washington, D.C.: ASM Press; 2000.
  9. Mukherjee JS, Rich ML, Socci AR, Joseph JK, Viru FA, Shin SS, Furin JJ, Becerra MC, Barry DJ, Kim JY, Bayona J, Farmer P, Smith Fawzi MC, Seung KJ. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet. 2004; 363(9407):474-81.
  10. Dye C, Williams BG, Espinal MA, Raviglione MC. Erasing the world's slow stain: strategies to beat multidrug-resistant tuberculosis. Science. 2002 ; 295(5562):2042-6.
  11. Nunn P. The global control of tuberculosis: what are the prospects? Scand J Infect Dis. 2001;33(5):329-32.
  12. Glynn JR, Whiteley J, Bifani PJ, Kremer K, van Soolingen D. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg Infect Dis. 2002;8(8):843-9.
  13. Bifani PJ, Mathema B, Kurepina NE, Kreiswirth BN. Global dissemination of the Mycobacterium tuberculosis W-Beijing family strains. Trends Microbiol. 2002 Jan;10(1):45-52.
  14. Victor TC, de Haas PE, Jordaan AM, van der Spuy GD, Richardson M, van Soolingen D, van Helden PD, Warren R. Molecular characteristics and global spread of Mycobacterium tuberculosis with a western cape F11 genotype. J Clin Microbiol. 2004;42(2):769-72.