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

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Dissecting bacterial host interaction

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.

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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.

Keywords

Listeria monocytogenes, interferon response, multi-drug transporters, cell wall stress, macrophages

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