Estudi de la latència de mycobacterium tuberculosis en models experimentals de ratolí i in vitro
The most striking virulent organism in the world is Mycobacterium tuberculosis because it kills 2 million people every year all alone. An effective treatment and vaccine are available, but 1.800.000.000 people are still infected in the world, just a third of the world population.
Tuberculosis only develops in 10% of immunocompetent people, so a resistant phenotype is shown. So, we have to look for a resistant model to resemble these conditions. On the one hand, mice resistant strains to tuberculosis are a good model for this study.
An inactivated macrophage is not able to kill M. tuberculosis and allows the exponential growing and surivival inside phagosome in absence of an effective immune response. On the other hand, correctly activated macrophage acts as an effective destroy machine by acidificaction of phagosome, reduction condition, hydrolases and hazard effects of ROIs and RNIs. These mechanisms of destructions do not seem to be totally effective and thats the reason why we have to talk about latent infection. These bacilli must remain in those conditions allowing immune response not to recognise them and rising as one of the most striking problems in tuberculosis, latency.
According to actual hypothesis about dynamic population in granulomes that are the basis for the treatment of tuberculosis, some semi-latent population would be present in granulomatous injuries extracellularly at pH lower than 5,5. This population would be one of the main reason for the treatment fail in conjunction with latent bacilli. Thats the reason why the study of acidification susceptibility in an in vitro model may allow us to deeply know the bacilli behaviour in front of stress mechanisms. M. smegmatis has been studied in order to determine its answer to those conditions, but not M. tuberculosis. All strategies performed are based on a acid shock, this is a fast adaptation, but this situation does not resemble real conditions. I mean that adaptation to acidic conditions is related to a process of several hours (about 6). Moreover, phagosome maduration and phagolysosome formation is a slow process that requires long time. So, this time modulation must be taken into account. In the same way, the killing of M. tuberculosis may not be a fast process, this is, bacilli are able to overcome acidification for some days and so on. Eventually, the performing of this idea in the murine model is related to a metabolic adaptation of M. tuberculosis and must be useful for the confirmation of in vitro results.
This study is trying to add some more ideas about the latent bacilli at genetic and immunologic level based on metabolism studies and answer to stress in an in vitro and in vivo model. The essential objective is to look for moleculars markers that may allow to define the presence of latent bacilli in tissues. In detail, this study has monitored the evolution of more than 60 genes of M. tuberculosis related to the acidic response that may resemble conditions in phagosomes from macrophages. Later, this expression has been followed up in a murine mode according to the conditions studied before. On the other hand, the immune response has been studied according to the expression of 24 cytokines related to tuberculosis. Previously, we have compared the behaviour of M. tuberculosis in two different strains of mice providing evidence of a resistant model for C57BL/6 mice.
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Advisor:Cardona, Pere Joan
School:Universitat Autónoma de Barcelona
Source Type:Master's Thesis
Keywords:409 departament de genetica i microbiologia
Date of Publication:07/16/2004