Timo Oosenbrug started as the first NWO-IIT PhD student.
His research project is funded by the NWO graduate programme awarded to the profile area Immunity, Infection & Tolerance.
PhD candidate: Timo Oosenbrug (MCB)
Starting date: 1st February 2016
Supervision: Maaike Ressing, Rob Hoeben (MCB)
Collaboration: Sjaak Neefjes (NKI), Sander van Kasteren (LIC)
Title and summary of the project:
“Unravelling mechanisms that control antiviral TLR signaling in time and space”
Host defense against infection critically depends on the innate immune system, which senses invading pathogens through pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are PRRs that have emerged as key sensors to microbes, for example recognizing components of DNA viruses such as nucleic acids and envelope glycoproteins. Adequate TLR responses elicit beneficial antimicrobial effector functions while preventing destructive uncontrolled inflammatory responses.
The output of TLR stimulation is dictated by a variety of factors, including the receptors’ subcellular localization. Inadequate trafficking of TLRs and/or their ligands is implicated in recurrent or lethal viral infections, highlighting the importance of spatiotemporal regulation of TLR activation in shaping a response of appropriate quality (specificity, amplitude and duration).
What are the factors and pathways governing the spatial and temporal organization of TLR signaling as well as its impact on TLR signaling output?
This project intends to employ an innovative approach to address these questions. By combining microscopy and biochemical experiments with chemical immunology in a multidisciplinary approach, we will unravel how TLR trafficking and interactions in “time and space” contribute to establishing tailored innate antiviral immunity. Subsequently, the interplay between these cellular processes and viral infection will be investigated.
This line of research may yield novel therapeutic opportunities to narrowly control specific TLR responses to combat viral infection while reducing the likelihood of triggering autoimmune disease.
Specific aims of the project (depicted in Figure 1):
- Establish a new system to study spatial control of TLR signaling in human cells.
- Identify cellular components that govern compartment-specific TLR signaling.
- Determine TLR signaling dynamics using novel synthetic photoactivatable ligands.
- Delineate how the newly identified cellular processes governing TLR signaling interact with DNA viruses.
Figure 1. Visual outline of the project