Team:CongoDRC-Bel Campus/Project

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ABSRTACT

NB. We have two differents approaches for this project: modelling transmission and engineered mycobacterial vaccine.

1.TRANSMISSION

      Buruli Ulcer (BU) is a debilitating disease that mainly affects the skin but which can also affect the bone.  The causative agent is called Mycobacterium ulcerans, which although different, belongs to the same family of organisms that cause leprosy and tuberculosis.  This affection is one of the most common mycobacterial diseases in human health.  Several cases of BU have been identified in at least 26 countries in the African Region since the early 1940s.  However, in recent years, an increasing number of cases have been recorded in nearly all Western Africa countries, along the Gulf of Guinea. The causative agent is Mycobacterium ulcerans. For it to cause disease, it must either be transmitted from one infected individual directly to another     (e.g.; direct contact) or through the environment (e.g.; via an intermediate host) to a susceptible host. It must also have the capability of surviving and multiplying in either the environment or the host or in both.

Generally, the reservoir of infection is not exactly known but is believed to be either the sick individual or the environment, especially marshy soil and vegetation along slow-flowing streams and rivers, or perhaps an intermediate host that thrives in such environment conditions. The latent period for infection to progress to disease in the susceptible host is also not well known. The mode of transmission is not entirely known. Recent evidence suggests that certain aquatic insects (aquatic bug) belonging to the genus Naucoris and Diplonychus may be involved in the transmission of the infection. The causative agent is commonly introduced into the skin (from surface contamination) through traumatic breaches in the skin (irrespective of size). However, it is not well understood whether infection can occur directly through the intact skin, after an insect bite, or by direct person –to-person contact.

    One interesting hypothesis concerns the possibility of transmission by some aquatic species. Nevertheless, this bacteria it’s environmental, the simple hypothesis is the direct transmission of M.ulcerans by contaminated water. To identify the more probable way of transmission of M.ulcerans in environment, we rely on data and mathematical modeling transmission of M.ulcerans. Using Synthetic biology approaches we managed to build two different epidemiological models taken account of these two ways of possible transmission. The first model concerns the “environmental” transmission by contact with mycobacteria, through contaminated water. The second epidemiological model concerns the transmission of mycobacterium by ecological “networks”. The parameters of these two epidemiological models will be estimated from data of field with the more probable mode of transmission.

2.VACCINE.

M. ulcerans causing by B.U. This infection can be treated with multi drugs regime (rifampicin and streptomycin) but this is often associated with induced antibiotic resistance and does not protect individuals from re-infection Vaccination against M. ulcerans can therefore be aviable alternator to control this wide spread infection. However, developing an effective vaccine against M. ulcerans has presented a challenge because M. ulcérans or its components, which have frequently been used as parts of vaccines, are modified by mycobacterium such that they avoid host defense mechanism using synthetic biology approaches, we managed to assemble functional ‘’immunobrick’’ into a designer vaccine with a goal to activate both innate and acquired immune response to M. ulcerans. We propose developing two forms of such designers’ vaccines. -One will be based on modifying M. ulcerans component such that it can now recognize by the immune system. -The other relied upon linking M. ulcerans component to certain molecule of the innate immune response (so called Toll like receptor) to activate and guide M. ulcerans proteins to relevant compartments within the immune cell causing optimal innate and acquired immune response. An effective vaccine against M. ulcérans is not available, although it will be a durable solution. M. ulcerans avoids the immune surveillance by modifying several of this components including LAM (lipoarabinoman) ,SL1(sulfolipide 1) mycolactone to avoid detection by several Toll Like Receptor. The goal of our project was to prepare a modular designer vaccine using the principal of synthetic immunology. An effective vaccine was to trigger activation of adaptive immunity, against microbial proteins (mycolactone), polysaccharides or lipids metabolites (PDM: phtiocerol dimycocerosate, PGL: phenolglycolipide, SL1: sulfolipide 1, GPL: glycopeptidolipide) as well as innate immunity, with which is usually achieved by addition of adjuvant of whole microbes. We prepared a set of ‘immunobricks’ with the defined functions in activation of the immunosystem and can be combined to active a desired response. In the first approach, we want to modify the components M.ulcerans wall (LAM, SL1, PGL, PDM, and GPL) to be able to active TLR 2 making it visible to the immune system.

Project Details

Part 2

The Experiments

Part 3

Results