The Synaptic Leap

Tuberculosis (Edinburgh, Scotland), Vol. 87, No. 4. (July 2007), pp. 384-390.

The control of ammonia assimilation in Mycobacterium tuberculosis is poorly understood. We have been investigating a regulatory cascade predicted to control the activity of glutamine synthetase (GS). We previously demonstrated that the GS-modifying protein, GlnE (an adenylyl transferase), is essential for M. tuberculosis growth. GlnD, a uridylyl transferase, is involved in the control of GlnE activity in other bacteria. In M. tuberculosis, glnD is arranged in an apparent operon with amt and glnB; all three genes are up-regulated in a low-ammonia medium. We constructed an in-frame deletion of glnD by homologous recombination. The mutant had no growth defect in media containing different nitrogen sources. Total GS activity in culture filtrates was markedly reduced in the mutant, although activity in cell-free extracts remained normal. Virulence was unaffected in both in vitro and in vivo model systems of infection, indicating that the presence of extra-cellular GS is not critical for virulence and that the residual intra-cellular GS activity is sufficient. Thus although GlnD does play a role in the control of ammonia assimilation, it is not required for virulence.
Rose Read, Carey Pashley, Debbie Smith, Tanya Parish

The International Journal of Tuberculosis and Lung Disease, Vol. 10, No. 4. (April 2006), pp. 415-421.

SETTING: Under-ascertainment and under-reporting of tuberculosis (TB) hampers surveillance and control. Case detection is improved by record linkage of case registers and under-reporting can be estimated by capture-recapture (CR) analysis.OBJECTIVES: To assess the completeness of the TB registration systems and estimation of TB incidence and under-reporting in the Piedmont Region of Italy in 2001.METHODS: Record linkage of the Ôphysician notification systemÕ, the TB laboratory register and the hospital records register, and subsequent three-sample CR analysis.RESULTS: Record linkage identified 657 TB cases; CR analysis estimated 47 (95%CI 31–71) unrecorded cases. Under-reporting of the `physician notification system' was estimated at 21% (95%CI 20–23). The overall estimated TB incidence rate was 16.7 cases per 100000 population (95%CI 16.3–17.3), varying according to the subset investigated: 12.7 for individuals from low TB prevalence countries and 214.1 for immigrants from high TB prevalence countries; 13.1 and 25.8 for persons aged < and ≥60 years, respectively; and 32.1 in Turin, the regional capital and 10.8 in the rest of the region.CONCLUSIONS: When multiple recording systems are available, record linkage and CR analysis can be used to assess TB incidence and the completeness of different registers, contributing to a more accurate surveillance of local TB epidemiology.
I Baussano, M Bugiani, D Gregori, R van Hest, A Borraccino, R Raso, F Merletti

The International Journal of Tuberculosis and Lung Disease, Vol. 11, No. 3. (March 2007), pp. 289-292.

SETTING: Tuberculosis (TB) program in Ensenada, Mexico.OBJECTIVE: To evaluate the impact of the DOTS strategy on adherence and cure rates in everyday practice.DESIGN: Retrospective analysis of 629 patients diagnosed with TB.MEASUREMENTS AND RESULTS: A total of 70% of the patients under directly observed treatment (DOT) were cured vs. 72.8% of those under self-administered treatment (SAT, P = 0.57). There was no difference on the length of therapy according to treatment regimen (4.82 ± 2.41 for DOT vs. 4.93 ± 2.16 for SAT, P = 0.61); 16.8% of patients under DOT abandoned treatment vs. 14.1% in the SAT group (P = 0.40). Logistic regression analysis confirmed the previous findings, with length of treatment under 6 months being the strongest predictive variable for treatment failure (OR 18.8, P < 0.00). The type of regimen (DOT vs. SAT) was not predictive of treatment failure (OR for failure for SAT regimen 0.65, P = 0.14).CONCLUSIONS: Cure and completion of treatment rates in our population under study did not differ significantly when comparing DOT vs. SAT. Those in charge of the DOTS programs in a given country need to assess which are the most important ingredients for success in their particular program.
P Radilla-Chavez, R Laniado-Laborin

Tuberculosis (Edinburgh, Scotland), Vol. 87, No. 4. (July 2007), pp. 384-390.

The control of ammonia assimilation in Mycobacterium tuberculosis is poorly understood. We have been investigating a regulatory cascade predicted to control the activity of glutamine synthetase (GS). We previously demonstrated that the GS-modifying protein, GlnE (an adenylyl transferase), is essential for M. tuberculosis growth. GlnD, a uridylyl transferase, is involved in the control of GlnE activity in other bacteria. In M. tuberculosis, glnD is arranged in an apparent operon with amt and glnB; all three genes are up-regulated in a low-ammonia medium. We constructed an in-frame deletion of glnD by homologous recombination. The mutant had no growth defect in media containing different nitrogen sources. Total GS activity in culture filtrates was markedly reduced in the mutant, although activity in cell-free extracts remained normal. Virulence was unaffected in both in vitro and in vivo model systems of infection, indicating that the presence of extra-cellular GS is not critical for virulence and that the residual intra-cellular GS activity is sufficient. Thus although GlnD does play a role in the control of ammonia assimilation, it is not required for virulence.
Rose Read, Carey Pashley, Debbie Smith, Tanya Parish

The International Journal of Tuberculosis and Lung Disease, Vol. 13, No. 11. (November 2009), pp. 1320-1330.

The increasing emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) in the era of human immunodeficiency virus (HIV) infection presents a major threat to effective control of TB. Drug resistance in Mycobacterium tuberculosis arises from spontaneous chromosomal mutations at low frequency. Clinical drug-resistant TB largely occurs as a result of man-made selection during disease treatment of these genetic alterations through erratic drug supply, suboptimal physician prescription and poor patient adherence. Molecular mechanisms of drug resistance have been elucidated for the major first- and second-line drugs rifampicin, isoniazid, pyrazinamide, ethambutol, the aminoglycosides and the fluoroquinolones. The relationship between drug resistance in M. tuberculosis strains and their virulence/transmissibility needs to be further investigated. Understanding the mechanisms of drug resistance in M. tuberculosis would enable the development of rapid molecular diagnostic tools and furnish possible insights into new drug development for the treatment of TB.
Y Zhang, WW Yew

Tuberculosis (Edinburgh, Scotland) (31 December 2009)

Due to the complexity of the immune response to a Mycobacterium tuberculosis infection, identifying new, effective therapies and vaccines to combat it has been a problematic issue. Although many advances have been made in understanding particular mechanisms involved, they have, to date, proved insufficient to provide real breakthroughs in this area of tuberculosis research. The term "Translational Systems Biology" has been formally proposed to describe the use of experimental findings combined with mathematical modeling and/or engineering principles to understand complex biological processes in an integrative fashion for the purpose of enhancing clinical practice. This opinion piece discusses the importance of using a Translational Systems Biology approach for tuberculosis research as a means by which to go forward with the potential for significant breakthroughs to occur.
Judy Day, Larry Schlesinger, Avner Friedman

PLoS Pathog, Vol. 5, No. 10. (26 October 2009), e1000600.

Renewed efforts in tuberculosis (TB) research have led to important new insights into the biology and epidemiology of this devastating disease. Yet, in the face of the modern epidemics of HIV/AIDS, diabetes, and multidrug resistance—all of which contribute to susceptibility to TB—global control of the disease will remain a formidable challenge for years to come. New high-throughput genomics technologies are already contributing to studies of TB's epidemiology, comparative genomics, evolution, and host–pathogen interaction. We argue here, however, that new multidisciplinary approaches—especially the integration of epidemiology with systems biology in what we call “systems epidemiology�—will be required to eliminate TB.
Iñaki Comas, Sebastien Gagneux