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This report will aim to outline and summarise the current medical and scientific literature with regards to the infectious disease: Tuberculosis. The pathogenicity and virulence of TB's causative agent Mycobacterium Tuberculosis will be explained, along with its current epidemiology in the UK (and around the world). The current vaccine protocols and treatment regimen designed to combat the disease will be explained and evaluated for their effectiveness, with a final summary drawn regarding recommendations to the government for short and long term funding priorities.
Epidemiology: The scope of the problem and current world issues
Caused by the pathogen Mycobacterium Tuberculosis, TB is an infectious disease affecting the world over. In its active form it can lead most notably to pulmonary infections (around 75%), but can also affect other body systems and produce a more dangerous disseminated disease (miliary TB). The initial infection itself does not always lead to disease, indeed only 10% progress immediately to a primary infection, with 90% of those that come into contact with the pathogen developing only a latent infection. The risk of a latent infection must however not be underestimated, with the risk of reactivation very high in some groups.
In 2009, 9.4 million new cases of TB were documented, with an associated 1.7 million deaths. This figure comes after years of intervention and publicity from the World Health Organization, whose "Stop TB Strategy" aims to eliminate the infection by 2050. It is estimated around a third of the global population currently have a latent TB infection and although historically TB incidence has been associated with Less Economically Developed Countries, rates of TB in the UK rose again in 2009 by 4.2% (equating to 9,040 cases in 2009) . This trend can be attributed to the raised incidence of HIV/AIDS in the UK (with the associated immuno-compromisation leading to latent TB reactivation), increased incidence of other immune-compromised states (e.g. patients being treated for cancers), immigration (highlighted by the increasing TB trend localized to areas of Britain with large subpopulations of Asian/African migrants, e.g. London and Leicester), and perhaps to a degree, by the increased rates of diabetes in the UK (with diabetes trebling the risk of active TB formation following infection). All of these factors resulted in the highest rates of TB seen in the UK for nearly 30 years in 2009.
A vaccine and a standard drug regimen is available for TB, but becoming more prevalent are cases of TB consisting of strains with multi-drug resistance (MDR-TB) or with extensive drug resistance (XDR-TB). These strains have developed through misuse of the standard drug treatments and present an even greater threat. The exact figures of MDR-TB and XDR-TB are hard to quantify worldwide, but in the UK rates of MDR-TB strains have increased by 50% since 2000, with multi drug resistance seen in 58 cases in 2009.
As mentioned previously, the association between HIV/AIDS with the active form of TB is undeniable. What's more, TB was one of the biggest killers of HIV/AIDS patients in 2009 and presents a major obstacle in trying to ensure acceptable life-spans and life-styles for AIDS patients.
TB Pathophysiology - Infection, Survival, Replication
Mycobacterium tuberculosis is an intracellular bacterium. Its waxy outer coating composed of mycolic acid, makes standard classification techniques difficult (such as gram staining, as the dye is not retained), thus acid fast is used. It is a highly aerobic organism, with the lungs therefore providing a perfect environment for growth. Spread of the bacteria is typically through air droplets expelled from infected individuals through a symptomatic cough/sneeze which is only present in those with an active TB infection. Those with a latent infection (presence of mycobacterium within a lesion, held in a dormant/non-replicating state) are not "contagious", but can become so if the infection reactivates.
When the Mycobacteria enter the respiratory tract, they enter the terminal alveoli and are phagocytosed by pulmonary macrophages and dendritic cells. This uptake is dependent on Pathogen Associated Molecular Patterns (PAMP's) common among many pathogens, recognised by innate cellular receptors such as Toll-like receptors. These receptors recognise standard virulence factors in the pathogenic mycobacteria, such as peptidoglycan, lipopolysaccharide and certain DNA sequences known as CpG motif's (TRL2, TLR 4 and TLR 9 respectively), the activation of which mediate intra- and extra- cellular signalling to bring about a pro-inflammatory response (through TNFÎ±, IL-1 and IL-12 mediated effects) and directs the cells defences against the Mycobacteria. Activation of TLR 2 for example, increases expression of vitamin D receptors which leads to an increase in cathelicidin - an antibacterial polypeptide which kills MTB.
Once inside the macrophage phagosome, the Mycobacteria have the capabilities to continue replicating at a rate of once every 25 to 32 hours. This initial infection site constitutes the primary complex which includes any resultant hilar lymphadenopathy (Ghon's complex), regardless of its progression to post-primary tuberculosis. The infected macrophages and dendritic cells present MTB antigens to the recruited T cells (MHC II complexes to CD4+ cells) and leads to the cell-mediated immunity. This involves the formation of granulomas, constituting the macrophages undergoing frustrated phagocytosis surrounded by lymphocytes, localizing the MTB infected cells to the initial infection site. In the majority of infections, these granulomas will compromise blood supply to the centre, producing an anaerobic environment, leading to cellular degeneration and necrosis, with a caseous appearance. Despite this level of necrosis, MTB can survive within this site in a non-replicating dormant state, with the granuloma often becoming fibrotic, characterizing the latent infection. Recent research suggests this dormancy may involve formation of spore like structures that mediate survival throughout human host lifestyle, as occurs in other Mycobacteria. Subsequent fibrosis and calcification further excludes the Mycobacteria from the adjacent lung tissue (Ranke complex).
In around 5% of patients the above mechanisms do not succeed and the infection progresses to primary disease. This can be further exacerbated through spread of infected dendritic cells throughout lymph nodes and blood vessels, to other viscera.
CD4+ cells and their key cytokine INFÎ³ have a key role in the cell-mediated immunity targeted towards infected macrophages. Apoptosis of macrophages is brought about by Fas/Fas ligand binding mediated by CD4+, which also regulates destruction via CD8+ cells through the granulysin and resultant perforin release (which destabilizes the cell membrane). IFNÎ³ functions to increase antigen presentation in macrophages, as well as increasing macrophage function with regards to lysosome, killing intracellular MTB. Another critical cytokine is TNFÎ±, which acts to increase bacteriocidal activity of macrophages by increasing reactive nitrogen species within the cell and in producing an effective granuloma. This explains why patients being treated with anti-TNF treatment (e.g. Infliximab for Crohn's disease) have a high incidence of reactivated TB infections.
MTB has evolved through time to target crucial defence mechanisms, to prolong its life cycle and replication opportunities. These focus on key areas such as:
Changes in phagosome environment and maturation: the standard anti-mircobial properties of phagosomes rely on an acidic pH brought about by specially recruited H+-ATPase. This poorly understood process is believed to be altered by MTB, to bring about a reduction in inter-phagosome acidity. Similarly, the normal development from phagosome into phagolysosome for bactericidal processes is dependent on a raised intracellular calcium, resulting in activation of an enzyme (PI-3P) that phosphorylates a key phagosome membrane protein (PI-3K). This stage in phagosome maturation is evaded by MTB via SapM - which inactivates PI-3P. Furthermore, the MTB protein nucleoside diphosphate kinase (Ndk) reduces activation of Rab5 and Rab7, two intra-phagosome proteins which have effector functions involved in phagosome-lysosome fusion (Early Endosome Antigen 1 and Rab7-interacting lysosme protein respectively). Other virulent MTB proteins acting to prevent phagolysosome formation act on PI-3P in a similar way to HIV, with the similarities in pathogenesis contributing to increased risk of TB in HIV infected individuals. Finally, the ability for MTB contained in phagosomes to recruit a tryptophan-aspartate coat (TACO) on the phagosome, further prevents lysosome binding.
Prevent antigen presentation: an adequate cell-mediated response to MTB is reliant on presentation of antigens to CD4+ cells via MHC II complexes. This process is targeted by MTB proteins such as ManLAM (which also inhibits phago-lysosome formation) and 19kDa lipoprotein (lpqH) which reduce the efficacy of IFNÎ³, a cytokine crucial to antigen presentation.
Prevention of destruction: MTB destruction can occur intracellularly through phagolysosome action, via reactive nitrogen/oxygen species, or through macrophage apoptosis. The effects of the reactive nitrogen/oxygen species are overcome by the increased transcription of many genes designed to neutralise compound such as nitric oxide. These include DIaT, AhpC/D and Lpd which act together as a reductase. In addition, MTB genes Rv3654c and Rv3655c have been found to have a secretory property that has a role in preventing apoptosis of infected macrophages.
Escape from Phagosome: This is mediated by two proteins: ESAT-6 and CFP-10. These proteins are encoded for by a region known as RD1, and are believed to work by compromising the stability of the phagosome membrane contributing to MTB's escape. The two proteins are secreted as an ESAT-6:CFP-10 complex from MTB into the phagosome, where under acidic pH they disassociate from each other. ESAT-6 is the virulent protein that inserts into the membrane, leading to lysis and culminating in MTB's diffusion out of the phagosome. ESAT-6 then has further functioning, in enabling MTB to escape the cell altogether, by degrading the cell membrane of type I and II pneumocytes and contributing to localised spread. Genes such as ESAT-6 located in the RD1, are absent from the widely used BCG vaccine and if introduced to new developing vaccines, could increase the resultant protective potential.
Current vaccines and treatment regimens
Before 2005, all children in the UK were vaccinated against M.Tuberculosis with the BCG vaccine. Currently however, only those at "high risk" receive the vaccine (e.g. healthcare workers, infants who live in a region with high TB rates etc...). The vaccination itself consists of a live attenuated strain of bovine Mycobacterium Bovis, cultured over many years, to remove much of its virulence. The strain contains antigens similar to that of M.Tuberculosis, invoking an immune response and priming the immune system for future interaction with those specific antigens. Crucially however, recently discovered antigens, believed to be of great importance in the virulence of MTB (such as ESAT-6 described previously) are absent from the vaccine. As such, the BCG vaccine provides no immunity to these antigens. Historically, the vaccine has been used in many countries as a preventative measure against TB infection, but has received wide spread criticism for its effectiveness. It appears particularly effective at preventing the more serious forms of TB such as meningeal TB and miliary TB, but affords less immunity against the more common pulmonary type.
Latent tuberculosis is a large problem. Although those with a latent infection are not contagious, reactivation (especially among those that are immune-compromised) is possible. The current protocols as outlined by NICE state a treatment for individuals diagnosed with a latent TB infection should be implemented in those younger than 36, or any age if HIV+ or healthcare workers. The treatment typically involves six months of a hepatotoxic drug: Isoniazid. This explains the lack of treatment for over 35's and highlights an area for future research.
For those who develop the active form of pulmonary TB, the standard regime is six months of Isoniazid and Rifampicin, with Pyrazinamide and Ethambutol for the first two months. The multi-drug regimen is designed to combat and lessen the effects of possible resistance, with a greater than 90% effectiveness. However, if prescribed doses are not completed, or incorrect treatments are offered, a multi-drug resistance can result (resistance to at least rifampicin and Isoniazid). All suspected TB patients in the UK are assessed for MDR-TB (Multi drug resistant TB) and if resistance exists, treatment regimes will be lengthened and adapted to include additional second line drugs, with possible side effects. Resistance to TB drugs is increasing and often involves a mutation in the target for the drug. Rifampicin resistance, for example, is due to mutations in the rpoB gene (the usual target for rifampicin), which has a vital function in RNA synthesis.
The cure rates are around 95% for the standard pulmonary TB infection however, were resistance exits, this figure can drop to 50%-70%. Extensively drug resistant strains (XDR-TB) result in even higher mortality rates. The scientific community must make finding drug targets for these strains a top priority.
Short and Long Term Funding Priorities
New interventions follow two main strategies: development of new vaccines and production of new drug treatments for MDR-TB and XDR-TB, preferably with a reduced treatment time than the standard 6 months+ regimen.
One interesting advancement in recent years is nano-based technology. Recent studies have shown the efficacy of administering drugs within nanoparticles results in a slower, more controlled release of antibiotics, and results in a 20-fold increase of active compound within cells. This is obviously vital when treating Mycobacteria. It is hoped this novel strategy will, at least for the time being, reduce the need for new drug and, it is hoped, will lead to a reduced pill burden. This approach is one that would benefit funding in the short term, but may also warrant long term input regarding its potential use in administering new vaccines.
Another topic for discussion is the route through which the BCG vaccination is administered. Recent studies show aerosol immunization could provide better immunity focused at pulmonary tissue, with mice vaccinated via the aerosol route with "Mycobacterium w" being afforded a better immunity against TB than a standard BCG vaccine. Additional funding may help to evolve this area of research and to further explore and overcome potential problems with immunopathology that this strategy may present.
In terms of long term funding priorities, a more effective vaccination programme is the primary goal. The ideal scenario would be a vaccine that is cheap, effective and can be distributed worldwide to potentially eradicate the disease. 11 vaccines are currently involved in clinical trials, with new compounds that could act as targets for new vaccines being discovered frequently, e.g. EspC, an MTB secreted protein absent from BCG. Currently, 2 new live recombinant vaccines that are designed to over-express highly virulent antigens (rBCG30 and VPM1002) have begun their clinical trials and have been shown to afford better immunity in mice models than the standard BCG vaccination. Other potential candidates use vectors to introduce new antigens to boost the protection afforded by BCG. Another area that requires funding long term, is vaccinations that can help eradicate latent infections/prevent progression to full blown TB. One such candidate is Ag85B-ESAT6 vaccine, which includes the ESAT6 antigen discussed previously.
Finally then, if any of these proposed vaccinations/treatments are to find their way to a global market, funding must be made available to help with the process of human clinical trials, including recruitment and logistics, as well as an adequate distribution strategy to reach the most needy in the LEDC's.