Pathogens have been evolving with their hosts for millions of years adopting tailored strategies to propagate within the host body and evading the host immune response. It is crucial to understand the underlying strategies employed by pathogens on the cellular and molecular level in order to develop novel weapons against them. On the cellular level, host-pathogen interactions are generally very dynamic and tightly regulated. Therefore, it has been difficult to establish methodologies that can capture this cross-talk. To overcome these hurdles, we have been developing novel approaches to monitor the dynamic host-pathogen interactions. Our laboratory is taking advantage of fluorescent reporter molecules, which we use and/or develop to obtain information on molecular processes in single living cells. The key question of host cell invasion to be addressed will be (i) how do entero-pathogenic bacteria invade cells and (ii) how do the latter sense the incoming pathogens. First, we will use a novel assay to understand how an individual invading bacterium, such as Shigella hijacks host cellular machineries and ruptures the vacuolar membranes upon cellular uptake to escape into the host cytoplasm. Secondly, we will reveal how the change of intracellular localization of invasive pathogens impacts on the induced host immune response. Concerning this, we have established an assay to track the host gene expression response quantitatively (from any promoter of interest) during pathogen invasion in single cells with a timely resolution of seconds to minutes. Together, this will allow us to precisely understand the molecular mechanisms how invasive bacteria interfere with eukaryotic cellular trafficking and signal transduction pathways to alter host immune responses. Thus, beyond providing novel targets for antimicrobial therapy, our study will pave the way to understand fundamental cellular processes.
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