Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS

Final Activity Report Summary - MICROBAN (Microbial action on immune survival)

MICROBAN has been a success since all groups participated on the characterisation of mechanisms involved in the host-pathogen interactions. The network has focused its activities on two main pathogens: Salmonella and Mycobacterium with an emphasis on host response in dendritic cells.

The role of Salmonella effectors on innate and adaptive immune responses.
Salmonella enterica serovar Typhimurium (S. typhimurium) is an intracellular bacterium responsible for gastroenteritis in humans and for a typhoid-like illness in mice. Replication of Salmonella inside a vacuolar membrane requires the translocation of effector proteins into the host cell using a serynge and a needle called the type III secretion system. The first aim of the project was to discover the function of several of these effectors. In a collaborative effort between partner 1, 3, 4 and 7, four Salmonella effectors, SifA, PipB2, SeeJ and SopD2 were work targets. Results show that SopD2 antagonises the effects of SifA in terms of the stability of the vacuolar membrane and in transport of vesicles from the Salmonella-containing vacuole. These findings will give us further insights into the role of SifA, PipB2 and SopD2 and thus will help to determine how Salmonella regulates membrane transport and distribution around its vacuole.

Some clues suggest that Natural Killer (NK) cells are important in controlling Salmonella. Partner 3 showed that infected macrophages activate NK cells. Partner 2, 3 and 4 studied antigen presentation by MHC class I and MHC class II molecules. Here they studied how vesicles containing Salmonella move, how they contact MHC class II molecules and how they fuse to lysosomes in order to destroy the pathogens.

Consequences of Mycobacterium infection on innate and adaptive immune responses.
Partner 5 has tested a series of common kinase inhibitors for their effect on intracellular growth of Salmonella. Only the 'PKA-specific' inhibitor H-89 was able to inhibit intracellular growth. They synthesised a series of H-89 analogous and tested these for effects on intracellular growth of three pathogens; Salmonella, M.smegmatis and M.tuberculosis, in human macrophages. Combining in vitro kinase reactions from the hits with the various chemical inhibitors and considering the chemical profile for bacterial growth inhibition, we concluded that H-89 and its active analogous inhibited PKB/Akt1. Since this is a novel antibiotic target, we showed that MDR-M.tuberculosis could also be controlled by our compounds.

The granuloma is the hallmark of tuberculosis; however, its role in host defense against Mycobacterium tuberculosis (MTB) is poorly understood. In order to determine whether granulomas have lymphoid functions, mice lacking secondary lymphoid organs (SLOs) (splenectomised lymphotoxin beta receptor deficient mice) were infected with MTB and examined for their ability to generate antigen-specific immune responses. Results suggest that granulomas represent a type of tertiary lymphoid organ in which protective immune responses to MTB are primed.

Studying the role of dendritic cells in immune responses to pathogens:

During host-parasite interactions, dendritic cells (DCs) play a central role, as they are located in close contact with the mucosal surfaces where they can sample incoming pathogens. Partner 8 characterised how DCs interact with pathogens, and how DCs are transcriptionaly re-programmed following microbial activation. Activated DCs with Gram-negative bacteria and with Gram-positive bacteria were transcriptionally analysed with high-density oligonucleotide arrays that displayed probes for 22170 genes. Bioinformatics analysis showed modulation of about 1500 genes during the time course analysed and it was observed that Lactobacillus paracasei induced a very strong dendritic cells activation compared to other bacteria. In conclusion bacteria are able to induce a strong reprogramming in dendritic cells that maybe important in shaping the immune response.

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Parc Scientifique et Technologique de Luminy - Case 906
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