The innate immune system in Mycobacterium infection

The innate immune system provides an early response against invading microorganisms while the adaptive immune system operates at later stages when the pathogen has infected the host. In the first hours of exposure to and invasion by the pathogen, two outcomes can be schematically described: rejection/destruction of the pathogen (by innate immunity) and infection of the host (despite innate immunity). There are three fundamental aspects to consider upon contact with M. tuberculosis. In the first place M tuberculosis is allowed to enter the host or will be rejected which is probably decided by mechanisms inherent to the innate immune system. Later, invasion will lead to acute or to latent infection. This clinical latency often extends for lifetime of the individual. However, reactivation of the latent infection occurs in small but significant percentage (10%) in response to perturbations of the immune response, and active tuberculosis ensues. Our main objective is to understand the role of innate immunity in resistance and pathogeneses of Mycobacterium infections in patients and experimental models of infection. We will study the importance of TLR in the defence against primary mycobacterial infection and in the maintenance in the host-bacilli equilibrium in the chronic infection.

Mucosal immunity. IgA in protection against tuberculosis

Mycobacterium tuberculosis is the bacterium that causes tuberculosis in humans. Tuberculosis is probably the leading cause of death from infectious diseases worldwide; one third of the world's population is infected by M. tuberculosis that causes death of more than three million individuals per year. Several factors contribute to the recrudescence of tuberculosis i.e. HIV infections, socioeconomical factors, alcohol and drug abuse and, above all, the recent appearance of new strains multiresistant to the available anti-mycobacterial drugs. Unfortunately there is not, so far, a good vaccine against mycobacterial infections. The efficacy of BCG vaccination has been a subject of controversy since a large-scale analysis of randomized case-control trials of BCG showed variable results in different populations worldwide, with some studies pointing to 70% of efficacy and other studies none. One of the possible causes for this failure could be that the route of administration of the vaccine and the route of infection are different. The pulmonary route used by M. tuberculosis is not sufficiently protected when BCG is given systemically. Therefore, we are testing the hypothesis that intranasal immunization, by targeting the pulmonary mucosa, would be a higher local immune response and a stronger degree of protection. This idea is being supported by the European Commission.

Improved diagnosis of tuberculosis using non-invasive immune based methods

Tuberculosis (TB) has been affecting millions of people all over the world for many centuries and is currently the leading cause of death from a single infectious agent. Possibly, the current situation is the result of a number of failures such as poor efficacy of vaccination, unsatisfactory chemotherapy and, no secure diagnosis. Being TB frequently a pulmonary disease, the more relevant immunological reactions would take place in the lungs and associated lymphoid organs and secretions. Therefore, the immunological status of the individuals in relation to protection or infection should be tested preferentially in these organs and not in the serum or skin. Our goals are a) To increase our understanding of mucosal immunity which is required to explore the mode of infection by TB and to develop better diagnostic assays; b) to distinguish TB infection, latency, disease, protection and cure c) to develop new diagnostic methods based on the study of Mtb specific antibodies (particularly IgA) in mucosal secretions and serum.

Innate and adaptive immunity in clinical and experimental mycobacterial infection in neonates and infants

Tuberculosis is a leading killer world-wide, and the proportion of Paediatric tuberculosis is expanding. Although the BCG vaccine triggers specific T and B cell responses in neonates, it only confers protection from severe forms of tuberculosis in the first years of life. BCG does not significantly protect adults from pulmonary tuberculosis. There is therefore an urgent need to develop novel vaccines against tuberculosis, which would provide a long lasting protection following neonatal inoculation. One approach to this crucial aim is to decipher the mechanisms involved in neonatal immune responses to mycobacteria.

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