02 Research
Research
We study how innate immune cells detect threats, process those signals and mount protective responses. We combine genetics, cell biology, biochemistry and quantitative imaging, and we use synthetic biology to engineer the systems we study.
AREA 01 Toll-like receptor signaling
Myddosomes: how cells sound the alarm
How do innate immune cells turn the detection of a microbe into an appropriate response?
Toll-like receptors (TLRs) sense microbial and damage signals at the cell surface and within endosomes. Most TLRs signal through the adapter MyD88, which assembles into large complexes called myddosomes. We showed that myddosomes execute the entire TLR signaling pathway, and that the adapter TRAM releases them from receptors so that receptor-free myddosomes keep signaling in the cytosol.
We now ask how cells control when and where myddosomes form, how they are organized and how signaling is terminated. Each of these features tunes the strength, quality and duration of inflammation. We also use synthetic biology to engineer signaling complexes and test how their design shapes the response.
APPROACHHow we study it
CRISPR knock-in innate immune cells for endogenous TLR adapters, live-cell and super-resolution imaging, spatial proteomics, genome-wide CRISPR screens, and biochemistry.
WHY IT MATTERSFrom infection to autoimmunity
Too little TLR signaling leaves people vulnerable to infection, too much drives sepsis, autoimmunity and lymphoma. Because receptors initiate signaling but do not execute it, the myddosome offers control that receptor blockade never delivered.
CONNECTIONSBeyond TLRs
Inflammasomes, MAVS and cGAS-STING all signal through adapters that assemble cooperatively. The rules we establish for myddosomes may apply broadly across innate immune pathways.
AREA 02 Guanylate-binding proteins
GBPs: defense inside the cell
How do cells detect and defend against intracellular pathogens, without destroying themselves?
Interferon induces the expression of guanylate-binding proteins (GBPs). One family member, GBP1, can coat and disrupt intracellular bacteria and pathogen vacuoles, thereby enabling activation of cytosolic sensors and cell death induction. Because GBP1 acts on membranes, cells need to restrain it to prevent self-harm. We found that the kinase PIM1 phosphorylates GBP1 leading to its sequestration by 14-3-3σ. PIM1 is itself interferon-induced, so the same cytokine induces the effector and its regulator.
This network functions as a guard mechanism. Pathogens that subdue interferon signaling deplete PIM1 and release the defense they tried to disable. We now ask how GBPs choose their targets, resolve the structures that keep GBP1 inactive, and engineer GBP1 to redirect its activity against pathogens and tumors.
APPROACHHow we study it
Human innate immune cell infection models, proteomics, high-content imaging and AI-assisted image analysis, recombinant proteins.
WHY IT MATTERSLife or death decisions
Intracellular pathogens cause disease worldwide. GBP pathways decide whether an infected cell kills the pathogen, dies or survives, and the same pathways may enhance immune therapies against cancer.
CONNECTIONSEffector-triggered immunity
Plants detect infection by sensing sabotage of their own signaling rather than the pathogen itself. GBP1 shows that human cells do the same, and we ask how widely mammalian cells use this strategy.