Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, kills over 2 million people each year. It is estimated that approximately one-third of the world population is infected with M. tuberculosis, though the majority will never develop active disease. The most severe form of tuberculosis occurs when the bacterium spreads to the brain to cause meningitis. We examined whether the genetic variation of the person and the bacteria influenced the type of disease a person develops. We have previously shown that certain mutations in genes of the human immune system can predispose adults in Vietnam to developing tuberculous meningitis. In this study we show that some strains of M. tuberculosis commonly found in Europe and America are less likely to cause tuberculous meningitis in Vietnamese adults than strains predominantly found in Asia. We then looked at the interaction between M. tuberculosis strains and mutations in human immune genes and show that a particular mutation, TLR2 T597C, is more commonly found in patients infected with the East-Asian/Beijing strains of M. tuberculosis. This is the first study to look at both the host and pathogen genotypes together in tuberculosis infection, and the findings suggest that the outcome of exposure to M. tuberculosis can depend on both the human genotype and the bacterial genotype.

Many factors affect the severity of tuberculosis in infected individuals. Among these are the genetic make-up of the bacterial strain, that of the host, and the interplay between the two.

Entry into host macrophages and evasion of intracellular destruction mechanisms, including phagosome-lysosome fusion, are critical elements of Mycobacterium tuberculosis (Mtb) pathogenesis. To achieve this, the Mtb genome encodes several proteins that modify host signaling pathways. PtpA, a low-molecular weight tyrosine phosphatase, is a secreted Mtb protein of unknown function. The lack of tyrosine kinases in the Mtb genome suggests that PtpA may modulate host tyrosine phosphorylated protein(s). We report that a genetic deletion of ptpA attenuates Mtb growth in human macrophages, and expression of PtpA-neutralizing antibodies simulated this effect. We identify VPS33B, a regulator of membrane fusion, as a PtpA substrate. VPS33B and PtpA colocalize in Mtb-infected human macrophages. PtpA secretion combined with active-phosphorylated VPS33B inhibited phagosome-lysosome fusion, a process arrested in Mtb infections. These results demonstrate that PtpA is essential for Mtb intracellular persistence and identify a key host regulatory pathway that is inactivated by Mtb.

Researchers at the University of British Columbia and Vancouver Coastal Health Research Institute have discovered how tuberculosis (TB) bacteria hide and multiply in the human body and are working toward a treatment to block this mechanism of infection. TB causes disease by infecting the body’s macrophages. Normally, macrophages engulf bacteria and then release powerful digestive enzymes that destroy the bacteria. The researchers found that a protein secreted by TB targets a protein in the macrophage. In doing so, TB disrupts this process, allowing it to hide and multiply within the macrophage. The research, lead by Dr. Yossi Av-Gay, research scientist with the Immunity and Infection Research Centre at the Vancouver Coastal Research Institute and associate professor with UBC’s Faculty of Medicine, suggests that therapies that block the activity of the TB protein in macrophages would allow the body to identify TB bacteria more easily. This would prevent the establishment of active and latent tuberculosis and will lead to a new and more effective treatment for TB.

Background: Elucidation of the basic mechanistic and biochemical principles underlying siderophore mediated iron uptake in mycobacteria is crucial for targeting this principal survival strategy vis-à-vis virulence determinants of the pathogen. Although, an understanding of siderophore biosynthesis is known, the mechanism of their secretion and uptake still remains elusive. Methodology/Principal Findings: Here, we demonstrate an interplay among three iron regulated Mycobacterium tuberculosis (M.tb) proteins, namely, Rv1348 (IrtA), Rv1349 (IrtB) and Rv2895c in export and import of M.tb siderophores across the membrane and the consequent iron uptake. IrtA, interestingly, has a fused N-terminal substrate binding domain (SBD), representing an atypical subset of ABC transporters, unlike IrtB that harbors only the permease and ATPase domain. SBD selectively binds to non-ferrated siderophores whereas Rv2895c exhibits relatively higher affinity towards ferrated siderophores. An interaction between the permease domain of IrtB and Rv2895c is evident from GST pull-down assay. In vitro liposome reconstitution experiments further demonstrate that IrtA is indeed a siderophore exporter and the two-component IrtB-Rv2895c system is an importer of ferrated siderophores. Knockout of msmeg_6554, the irtA homologue in Mycobacterium smegmatis, resulted in an impaired M.tb siderophore export that is restored upon complementation with M.tb irtA. Conclusion: Our data suggest the interplay of three proteins, namely IrtA, IrtB and Rv2895c in synergizing the balance of siderophores and thus iron inside the mycobacterial cell.

Researchers from India led by Professor Seyed E Hasnain of the Institute of Life Sciences, at the University of Hyderabad, India have worked out the mechanism of iron uptake system of Mycobacterium tuberculosis, which is considered to be one of the important drug targets. Iron acquisition and regulation in intracellular pathogens especially mycobacterium is a central survival mechanism working at the interface of host-pathogen interactions and is, therefore, a promising target for intervention. However, the bottleneck so far in targeting this important survival strategy was the absence of understanding of the mechanism of iron acquisition and transport in mycobacterium.

Humans have been cozy with their cows for almost 10,000 years--milking them, herding them, and even sleeping with them for warmth. Many researchers have thought that cows also gave our ancestors a less welcome gift: their first exposure to the mycobacteria that cause tuberculosis (TB), a disease that kills 2 million people a year. At the meeting, a DNA study of 10 species of mycobacteria showed that early humans were infected with strains of Mycobacterium tuberculosis, which cause TB, long before they began herding cattle. That suggests that it was humans who transmitted the disease to bovids and other animals. "TB spread from humans to animals," perhaps when modern humans emerged from Africa to spread around the globe, reported graduate student Luz-Andrea Pfister of Arizona State University in Tempe in her talk.

Drug resistant tuberculosis is posing a growing threat in the UK, probably fuelled by immigration, say experts.

Health officials are blaming a rise in drug-resistant tuberculosis in Britain on immigration and inadequate measures to control outbreaks among prisoners and drug users. Cases of resistant strains of TB nearly doubled between 1998 and 2005, according to a study of 28,620 infections in England, Wales and Northern Ireland by the Health Protection Agency. Official figures showed that the number of people whose infection was resistant to at least one major drug rose from 170 in 1998 to 336 in 2005. The number of cases of multi-drug resistant TB also rose to 39 from 23 over the same period.