Type I interferons in innate immunity against bacteria

Type I Interferons (IFN-I) comprise a family of cytokines including the immunomodulators IFN-alpha and IFN- beta. IFN-I are produced when cells encounter pathogens and sense these using pattern recognition receptors (PRR). A variety of PRRs recognize microbial molecules either at the cell surface, within endosomal compartments, or in the cytoplasm. Listeria monocytogenes is a Gram-positive, rod-shaped bacterium that invades and replicates within cells of its host organism. Intracellular replication is made possible by the synthesis of molecules that allow disruption of endsomal or phagosomal organelles, such as the Listeriolysin O. Host cells recognize infection with L. monocytogenes with plasma membrane or endosme membrane-associated receptors, but also with an unknown cytosolic receptor. In most cell types, this latter receptor is instrumental in starting a signal transduction pathway that targets IFN-I genes. In previous work we and others have shown that IFN-I synthesis in Listeria-infected cells causes harmful effects to murine hosts and sensitizes them to lethal sequelae of infection. This differs from the situation with most other pathogens, particularly viruses, where IFN-I production is correlated with increased clearance and survival of the host organism. One reason for the harmful IFN-I effect is the increased propensity of IFN-I effector cells such as macrophages and T lymphocytes to succumb to an encounter with L. monocytogenes or its products. The main focus of this proposal is to understand how a mostly beneficial group of cytokines, the IFN-I, can turn villains in the case of L. monocytogenes infection. To this end we have designed experiments that will identify cells and signals contributing to IFN-I production in the Listeria-infected hosts. Furthermore, we propose complementary studies to identify cells responding to IFN-I during infection, thus transmitting the harmful character of IFN-I. It will be a long term goal to see whether producer and responder cells need to be in close apposition or whether a long range communication produces the adverse effect of IFN-I and whether it can be explained exclusively o the basis of enhanced effector cell death. To further understand the regulation of the cellular response to L. monocytogenes we propose to identify microRNAs expressed in infected cells and will determine whether a subfraction of these is regulated by IFN-I. Furthermore we will functionally inactivate the identified miRNAs and examine the consequences for the infected cell. Together our studies will contribute to a better understanding of the innate immune response to L. monocytogenes as an example of an intracellular, nonviral pathogen and to determine the reasons underlying the adverse effect of IFN-I.

Type I Interferons (IFN-I) comprise a family of cytokines including the immunomodulators IFN-alpha and IFN- beta. IFN-I are produced when cells encounter pathogens and sense these using pattern recognition receptors (PRR). A variety of PRRs recognize microbial molecules either at the cell surface, within endosomal compartments, or in the cytoplasm. Listeria monocytogenes is a Gram-positive, rod-shaped bacterium that invades and replicates within cells of its host organism. Intracellular replication is made possible by the synthesis of molecules that allow disruption of endsomal or phagosomal organelles, such as the Listeriolysin O. Host cells recognize infection with L. monocytogenes with plasma membrane or endosme membrane-associated receptors, but also with an unknown cytosolic receptor. In most cell types, this latter receptor is instrumental in starting a signal transduction pathway that targets IFN-I genes. In previous work we and others have shown that IFN-I synthesis in Listeria-infected cells causes harmful effects to murine hosts and sensitizes them to lethal sequelae of infection. This differs from the situation with most other pathogens, particularly viruses, where IFN-I production is correlated with increased clearance and survival of the host organism. One reason for the harmful IFN-I effect is the increased propensity of IFN-I effector cells such as macrophages and T lymphocytes to succumb to an encounter with L. monocytogenes or its products. The main focus of this proposal is to understand how a mostly beneficial group of cytokines, the IFN-I, can turn villains in the case of L. monocytogenes infection. To this end we have designed experiments that will identify cells and signals contributing to IFN-I production in the Listeria-infected hosts. Furthermore, we propose complementary studies to identify cells responding to IFN-I during infection, thus transmitting the harmful character of IFN-I. It will be a long term goal to see whether producer and responder cells need to be in close apposition or whether a long range communication produces the adverse effect of IFN-I and whether it can be explained exclusively o the basis of enhanced effector cell death. To further understand the regulation of the cellular response to L. monocytogenes we propose to identify microRNAs expressed in infected cells and will determine whether a subfraction of these is regulated by IFN-I. Furthermore we will functionally inactivate the identified miRNAs and examine the consequences for the infected cell. Together our studies will contribute to a better understanding of the innate immune response to L. monocytogenes as an example of an intracellular, nonviral pathogen and to determine the reasons underlying the adverse effect of IFN-I.