[1073] Innate Immunity Against Intracellular Pathogens

IFN-driven innate immunity against intracellular pathogens

How does an immune-activated cell recognise and eliminate an intracellular infection without attacking its own structures? How do infected cells get destroyed, but bystander cells survive? To answer these questions, we are studying the intracellular apicomplexan parasite Toxoplasma gondii and the bacterium Salmonella Typhimurium in infections of human host cell lines. These intracellular pathogens initially reside in vacuoles, which protect them from intracellular host immune recognition. During infection, proinflammatory cytokines such as interferon gamma (IFNγ) induce the upregulation of interferon-stimulated genes (ISGs), which play a role in the innate immune response to infection. In IFNγ-stimulated host cells, the combination of pathogen and host factors leads to the destruction of vacuole membranes and pathogens, which can result in programmed host-cell death pathways to eliminate the replicative niches of pathogens. A prominent class of ISGs that drives these pathways are 7 human large GTPases called the Guanylate Binding Proteins (GBPs). Some GBPs target intracellular membranes through mechanisms that are not completely understood, and the function of others remain undiscovered.

Our research addresses the regulation of innate immune defences across membranes of cells infected with Toxoplasma or Salmonella and their responses in uninfected bystander cells. We are studying how ISGs and specifically GBPs regulate Toxoplasma and Salmonella-induced host cell death and how GBPs distinguish pathogen-associated intracellular membranes from self-membranes. By answering these fundamental questions of intracellular immunity at membranes, we will generate knowledge to be exploited for the therapeutic targeting of infections or sterile inflammation derived from intracellular membrane damage.