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.
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:<p>Regulatory T cells (Tregs) expand during Mycobacterium tuberculosis (Mtb) infection and suppress T cell mediated control. Whether Mtb actively contributes to this process is unclear. Here, using a genome-wide mutant library, we show that expression of Mtb Rv1272c, an ATP-binding cassette transporter, increased under hypoxic condition, promotes Mtb survival in vivo by increasing lecithin import, followed by the production and release of linoleic acid. Linoleic acid released by infected macrophages promoted surface trafficking of the immune checkpoint molecule CTLA-4 in Tregs via the Ca²⁺ transporter ATP2a3. This in turn inhibited macrophage reactive oxygen species production and promoted Mtb survival inside macrophages. Rv1272c-induecd linoleic acid further promoted Mtb immune evasion via increasing CTLA-4 surface trafficking on Tregs in vivo. [AU please mention in vivo work on virulence as well] Mechanistically, linoleic acid interacts with ATP2a3 in Tregs and promotes mitochondria-associated endoplasmic reticulum (ER) membrane formation. This facilitates ER to mitochondrial Ca2+ transfer, depletion of Ca2+ in the ER, and triggers store-operated calcium entry, thus elevating cytosolic Ca2+ levels to increase Ca2+-dependent CTLA-4 surface trafficking in Tregs. These findings reveal that Mtb can use a metabolite to manipulate host responses and promote its intracellular survival.</p>