IMMUNITY TO LISTERIA

Mechanisms of innate immune activation of the intracellular bacterial pathogen L. monocytogenes

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 Obiettivo del progetto (Objective)

'A central problem in microbial pathogenesis is how cells of the immune system recognize and respond to pathogens, and conversely, how pathogens avoid and/or manipulate the host response. In order to approach this problem, we have chosen to focus on the interaction between the intracellular bacterial pathogen, Listeria monocytogenes and the immune cells, macrophages. Macrophages, express surface and cytosolic innate immune receptors that recognize conserved molecules of microbial origin, leading to induction of host inflammatory responses. Ironically, while macrophages are important effector cells of the immune system, they are permissive hosts for intracellular pathogens, and it is still not clear how they sense and respond to live intracellular pathogens. This research proposal aims to directly identify mechanisms by which intracellular pathogens activate the innate immune system. We recently performed a forward genetic screen for L. monocytogenes mutants that induce an enhanced or diminished host innate immune response. Using this unbiased approach we identified L. monocytogenes multi-drug resistance (MDR) transporters that controlled the magnitude of a host cytosolic surveillance pathway, leading to the production of Type I interferon response. In this research program we wish to continue with this approach and (I). Identify additional L. monocytogenes molecular determinants that involved in activation of host innate immune pathways. (II). Using genetic and biochemical approaches we will study the regulation and function of the newly identified L. monocytogenes MDRs in vivo and their role in activation of the Type I interferon response. (III). Identify bacterial ligands that activate the Type I interferon response. We hypothesize that bacterial ligands are transported by the MDRs to the host cytosol where they are recognized. We will use bacterial mutants over-expressing MDRs to identify the MDR-specific substrate(s).'

Introduzione (Teaser)

Identifying the molecular determinants of immune system activation during bacterial infection could have important consequences for therapy. A European study performed a genetic screen of Listeria mutants to determine the molecules that drive pathogen host invasion.

Descrizione progetto (Article)

Listeria are bacteria found in water and soil that can cause foodborne infections, posing a serious health problem worldwide.

Upon infection, bacteria are encountered by the immune cells which release proteins called interferons that mediate immune system communication and response.

Macrophages constitute the first line of defence against infection and engulf invading pathogens. They express certain receptors to induce host inflammatory responses but can also act as permissive hosts for intracellular pathogens.

The ?Mechanisms of innate immune activation of the intracellular bacterial pathogen L. monocytogenes.? (IMMUNITY TO LISTERIA) project aimed to study the interactions between the human intracellular bacterial pathogen and our innate immune system. To this end, genetic screening was done to identify molecular determinants that contribute to activation of host immune pathways.

Among the generated bacterial mutants with altered immune response, researchers identified a component of the bacterial secretion system that is critical for the production of virulent factors. Bacteria mutant to SecDF exhibited impaired translocation and spread, leading to a less virulent phenotype in animals.

Scientists were also interested in studying Listeria multidrug transporters (MDRs) as modulators of Type I interferon (IFN) response in macrophage cells. To this end, they screened various bacteria mutants with suppressed or enhanced IFN-beta response in macrophages.

The hypothesis was that bacterial ligands get transported by the MDRs to the host cytosol where they are recognised.

The data indicated the requirement of a cohort of MDR transporters that together contribute to the induction of type I IFN responses during infection. In the search for a physiological function of these transporters, the study revealed a role in cell wall stress responses. For instance, MDRs were found to regulate essential bacterial functions such as lipoteichoic acid (LTA) and peptidoglycan synthesis.

Taken together, the information generated during the IMMUNITY TO LISTERIA study improves our basic understanding of the complex interactions between immune cells and pathogens. The mutant strains may be utilised for the development of more potent vaccines.