The Synaptic Leap

Tuberculosis, Vol. 89, No. 4. (July 2009), pp. 285-293.

Summary The resurgence of tuberculosis worldwide has closely mirrored the HIV pandemic. In regions like sub-Saharan Africa, a large proportion of individuals are co-infected with Mycobacterium tuberculosis and HIV. Macrophages are the reservoir host cells  for both pathogens, however the interactions between both pathogens in co-infected cells remain poorly understood. Thus, the global gene responses of primary human macrophages following productive co-infection with highly purified HIV and M. tuberculosis were analyzed using cDNA microarrays. A broad range of genes was up-regulated in response to co-infection or M. tuberculosis infection of primary macrophages, including those encoding pro-inflammatory chemokines and cytokines, their receptors, signalling associated genes, type I IFN signalling genes and genes of the tryptophan degradation pathway. Real-time RT-PCR analysis confirmed up-regulation of a wide variety of genes including indoleamine 2,3 dioxygenase and Sp110 in M. tuberculosis and co-infected samples. Downstream analysis confirmed significant elevation of the chemokines CCL3, CCL4 and CCL8 in M. tuberculosis and co-infected culture supernatants. In contrast, the changes seen in gene expression following HIV infection alone were fewer in number and significantly less in magnitude. Thus, the effects of M. tuberculosis infection on global gene expression dominated the effects of HIV-1 in co-infected primary human macrophages.
Susan Maddocks, Gabriella Scandurra, Craig Nourse, Chris Bye, Rohan Williams, Barry Slobedman, Anthony Cunningham, Warwick Britton

Tuberculosis, Vol. 87, No. 5. (September 2007), pp. 393-404.

Summary Members of the Mycobacterium tuberculosis complex contain the transposable element IS 6110 which, due to its high numerical and positional polymorphism, has become a widely used marker in epidemiological studies. Here, we review the evidence that IS 6110 is not simply a passive or ‘junk’ DNA sequence, but that, through its transposable activity, it is able to generate genotypic variation that translates into strain-specific phenotypic variation. We also speculate on the role that this variation has played in the evolution of M. tuberculosis and conclude that the presence of a moderate IS 6110 copy number within the genome may provide the pathogen with a selective advantage that has aided its virulence.
C McEvoy, A Falmer, N Vanpittius, T Victor, P Vanhelden, R Warren

Science, Vol. 328, No. 5980. (14 May 2010), pp. 852-856.

Mycobacterium tuberculosis has a penetrance of its host population that would be the envy of most human pathogens. About one-third of the human population would have a positive skin test for the infection and is thus thought to harbor the bacterium. Globally, 22 "high-burden" countries account for more than 80% of the active tuberculosis cases in the world, which shows the inequitable distribution of the disease. There is no effective vaccine against infection, and current drug therapies are fraught with problems, predominantly because of the protracted nature of the treatment and the increasing occurrence of drug resistance. Here we focus on the biology of the host-pathogen interaction and discuss new and evolving strategies for intervention. 10.1126/science.1184784
David Russell, Clifton Barry, JoAnne Flynn

The international journal of tuberculosis and lung disease : the official journal of the International Union against 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