PART IIIB, Nobody does it better: Mycobacterium tuberculosis and persistence

“A principal reason that tuberculosis continues to be a major world health problem…— is its remarkable ability to persist in the body.”
--William R. Jacobs Jr, Howard Hughes Institute Medical Investigator, Albert Einstein College of Medicine3

William R. Jacobs, Jr., Ph.D. is a professor in both the Department of Genetics and the Department of Microbiology and Immunology at Albert Einstein College of Medicine in Bronx, NY. He has been nicknamed the “TB Terminator” due his skilled determination to vanquish M. tuberculosis. Dr. Jacobs’ laboratory of dedicated scientists and his collaborators have advanced the understanding of bacterial genetics and the nature of a subpopulation (0.1 percent) of bacterial survivors or “the persisters.” The key to conquering TB lies in stopping its persistence.

“Mycobacterium tuberculosis has the amazing ability to persist. T lymphocytes can keep the bacteria in check, but they don’t sterilize.” --William R. Jacobs Jr.6

The continual survival of persisters in human hosts is dependent upon their ability to escape immune surveillance. Persisters are not unique to M. tuberculosis, although probably no organism is better at the game. Persistence has been identified during infection both in vitro and in vivo as a phenomenon present in all bacteria that have been studied, including Salmonella, Pseudomonas, Bartonella, and Helicobacter. More recently, persisters have been demonstrated with the fungal pathogen, Candida albicans. Much of what is known about bacterial persistence has been learned through laboratory studies of persistence in Escherichia coli, and despite many new findings, the fundamental mechanisms of persistence along with applications to chronic infections are yet being revealed.

The first-responders in the immune response to TB are macrophages, a type of white blood cells that ingest the mycobacteria in the lung and make pieces of the TB bacteria visible on the infected cell surface, in order to recruit other infection fighters such as T lymphocytes. TB can persist inside macrophages for an extended time. The consequences of persistence include prolonged treatment and difficulty in treatment with conventional antimicrobials. It is usually assumed that persisters are non-replicating or just slowly growing; however, in reality, Dr. Jacobs says, it is difficult to distinguish between the two physiological states.

Dr. Jacobs’ resourcefulness and resolve are exemplified by his isolation of mycobacterial phages, viruses that infect and replicate in mycobacterial hosts, from the dirt in his backyard. One such phage Bxb1, the “Bronx Bomber,” has been used extensively in studies involving an Mtb relative, M. smegmatis, a valuable model of Mtb biology; the mycobacteriophage Bxb1 has been referenced in more than 29 scientific publications.

In collaboration with Dr. Graham Hatfull’s lab at the University of Pittsburgh, Bxb1 and other mycobacteriophages have been characterized. The Bxb1has been shown to specifically integrate into the groEl1gene, resulting in the disruption of biofilm formation. The Jacobs and Hatfull team have demonstrated that Mtb forms biofilms (surface attachment) with environmental and genetic characteristics distinctly different from free-floating (planktonic) growing cells. Moreover, they have found Mtb biofilms are drug-tolerant and contain persistent cells that remain viable in conditions of highly concentrated anti-TB antibiotics.

Recent research (4 January 2013 Science) by Yuichi Wakamoto of the University of Tokyo and Neeraj Dhar of the Swiss Federal Institute of Technology in Lausanne and colleagues, suggests that cell survival in the face of antibiotics is independent of growth rate and that many mechanisms of persistence exist. Their conclusions were based on studies using M. smegmatis.

Acknowledgements: The writer is most grateful to both Dr. Jacobs and Dr. Markova for sharing their keen insights in person/by telephone, and by e-mail, respectively. Dr. Hatfull is also thanked for his thoughtful suggestion to contact Dr. Jacobs, in the first place.

References and Read-more-about-it:

1. LaFleur MD, Kumamoto CA, Lewis K (2006) Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob Agents Chemother 50:3839–3846.
2. Dawson CC, Intapa C, Jabra-Rizk MA (2011) ‘‘Persisters’’: Survival at the cellular level. PLoS Pathoge 7(7): e1002121 ns.
3. HHMI, Howard Hughes Medical Institute. HHMI News: Research News. A Ringing endorsement for a new TB drug target. 27 April 2000. Available at: http://www.hhmi.org/news/jacobs2.html Accessed 11 January 2013.
4. HHMI, Howard Hughes Medical Institute. HHMI News: Research News. Enzyme offers target to attack drug-resistant tuberculosis.17 August 2000. Available at: http://www.hhmi.org/news/jacobs3.html Accessed 11 January 2013.
5. Miley M. AAAS Member Central. Member Spotlight. Bill Jacobs, the TB Terminator. 31 August 2012. Available at: http://membercentral.aaas.org/blogs/member-spotlight/bill-jacobs-tb-terminator%20Accessed%2011%20January%202013.
6. Berger A. (2000) Persistence of tuberculosis explained. BMJ 321(7259):469.
7. Ohja AK, Baughn AD, Sambandan D et al. (2008) Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol Microbiol. 69(1):164-174.
8. Noens EE, Williams C, Anandhakrishnan M, et al. (2011) Improved mycobacterial protein production using a Mycobacterium smegmatis groEL1ΔC expression strain. BMC Biotechnol. 11:27.
9. Zambrano MM, Kolter R. (2005) Mycobacterial Biofilms: A Greasy Way to Hold It Together. Cell 123:762-4.