Project description:Intracellular pathogens, such as Salmonella enterica serovar Typhimurium (S.Tm), are able to sense and respond to a changing host cell environment. Macrophages exposed to microbial products undergo metabolic changes that are increasingly understood to drive a productive inflammatory response. However, the role of macrophage metabolic reprogramming in bacterial adaptation to the intracellular environment has not been explored. Here we show that changes in host metabolic state serve as a signal detected byS.Tm. Using metabolic profiling and dual RNA-seq, we show that succinate accumulates in infected macrophages and is sensed by intracellular S.Tm to promote induction of virulence genes. Succinate uptake by the bacterium drives induction of pmrAB-dependent genes and SPI-2 virulence-associated regulon. S.Tm lacking the DcuB transporter for succinate uptake display impaired intracellular survival. Our work demonstrates that accumulation of metabolic intermediates, necessary for macrophage activation, promote intracellular survival of pathogens, opening a new realm of metabolic host-pathogen crosstalk.
Project description:Chemokine receptor 4 (CXCR4) is a member of the chemokine receptor family that is overexpressed in various cancer types and has been involved in cancer progression and metastasis. In light of recent findings suggesting that intracellular CXCR4 rather than CXCL12-CXCR4-operated signaling promotes cancer cell survival and accumulating evidence indicating that the trafficking and targeting of G protein-coupled receptors (GPCRs) to specific cellular compartments depends on their association with protein partners, we characterized the CXCR4 interactome in HEK-293 cells using an affinity purification-mass spectrometry (AP-MS) strategy. These studies identified Ephrin B1 as a major protein partner of CXCR4 that plays a key role in its intracellular localization and signal transduction.
Project description:Intracellular pathogens, such as Salmonella enterica serovar Typhimurium (S.Tm), are able to sense and respond to a changing host cell environment. Macrophages exposed to microbial products undergo metabolic changes that are increasingly understood to drive a productive inflammatory response. However, the role of macrophage metabolic reprogramming in bacterial adaptation to the intracellular environment has not been explored. Here we show that changes in host metabolic state serve as a signal detected byS.Tm. Using metabolic profiling and dual RNA-seq, we show that succinate accumulates in infected macrophages and is sensed by intracellular S.Tm to promote induction of virulence genes. Succinate uptake by the bacterium drives induction of pmrAB-dependent genes and SPI-2 virulence-associated regulon. S.Tm lacking the DcuB transporter for succinate uptake display impaired intracellular survival. Our work demonstrates that accumulation of metabolic intermediates, necessary for macrophage activation, promote intracellular survival of pathogens, opening a new realm of metabolic host-pathogen crosstalk.
Project description:Intracellular pathogens, such as Salmonella enterica serovar Typhimurium (S.Tm), are able to sense and respond to a changing host cell environment. Macrophages exposed to microbial products undergo metabolic changes that are increasingly understood to drive a productive inflammatory response. However, the role of macrophage metabolic reprogramming in bacterial adaptation to the intracellular environment has not been explored. Here we show that changes in host metabolic state serve as a signal detected byS.Tm. Using metabolic profiling and dual RNA-seq, we show that succinate accumulates in infected macrophages and is sensed by intracellular S.Tm to promote induction of virulence genes. Succinate uptake by the bacterium drives induction of pmrAB-dependent genes and SPI-2 virulence-associated regulon. S.Tm lacking the DcuB transporter for succinate uptake display impaired intracellular survival. Our work demonstrates that accumulation of metabolic intermediates, necessary for macrophage activation, promote intracellular survival of pathogens, opening a new realm of metabolic host-pathogen crosstalk.