Honors & Awards
CIHR Fellowship (Postdoctoral), Canadian Institutes of Health Research (2018-2021)
Vanier Canada Graduate Scholarship, Canadian Institutes of Health Research (2013-2016)
Frederick Banting and Charles Best Canada Graduate Scholarship, Canadian Institutes of Health Research (2013)
Ontario Graduate Scholarship, Government of Ontario (2012)
Queen Elisabeth II/ Aventis Pasteur Graduate Scholarship in Science and Technology, Province of Ontario/ University of Toronto (2011)
Bachelor of Science, Simon Fraser University (2011)
Doctor of Philosophy, University of Toronto (2017)
The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling
2019; 365 (6448): 47-+
Multiple cytosolic innate sensors form large signalosomes after activation, but this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We found that the eIF2α kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2α (eIF2α), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2α signaling axis was also essential for signaling downstream of the innate immune mediators NOD2, MAVS, and TRIF but dispensable for pathways dependent on MyD88 or STING. Moreover, filament-forming α-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2α, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK/eIF2α/HSPA5 axis of the endoplasmic reticulum UPR.
View details for DOI 10.1126/science.aaw4144
View details for Web of Science ID 000474432700029
View details for PubMedID 31273097
- Structure of the IFN gamma receptor complex guides design of biased agonists NATURE 2019; 567 (7746): 56-+
Structure of the IFNgamma receptor complex guides design of biased agonists.
The cytokine interferon-gamma (IFNgamma) is a central coordinator of innate and adaptive immunity, but its highly pleiotropic actions have diminished its prospects for use as an immunotherapeutic agent. Here, we took a structure-based approach to decoupling IFNgamma pleiotropy. We engineered an affinity-enhanced variant of the ligand-binding chain of the IFNgamma receptor IFNgammaR1, which enabled us to determine the crystal structure of the complete hexameric (2:2:2) IFNgamma-IFNgammaR1-IFNgammaR2 signalling complex at 3.25A resolution. The structure reveals the mechanism underlying deficits in IFNgamma responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFNgammaR2, which impairs assembly of the full signalling complex. The topology of the hexameric complex offers a blueprint for engineering IFNgamma variants to tune IFNgamma receptor signalling output. Unexpectedly, we found that several partial IFNgamma agonists exhibited biased gene-expression profiles. These biased agonists retained the ability to induce upregulation of major histocompatibility complex class I antigen expression, but exhibited impaired induction of programmed death-ligand 1 expression in a wide range of human cancer cell lines, offering a route to decoupling immunostimulatory and immunosuppressive functions of IFNgamma for therapeutic applications.
View details for PubMedID 30814731
Circulating NOD1 Activators and Hematopoietic NOD1 Contribute to Metabolic Inflammation and Insulin Resistance.
2017; 18 (10): 2415–26
Insulin resistance is a chronic inflammatory condition accompanying obesity or high fat diets that leads to type 2 diabetes. It is hypothesized that lipids and gut bacterial compounds in particular contribute to metabolic inflammation by activating the immune system; however, the receptors detecting these "instigators" of inflammation remain largely undefined. Here, we show that circulating activators of NOD1, a receptor for bacterial peptidoglycan, increase with high fat feeding in mice, suggesting that NOD1 could be a critical sensor leading to metabolic inflammation. Hematopoietic depletion of NOD1 did not prevent weight gain but protected chimeric mice against diet-induced glucose and insulin intolerance. Mechanistically, while macrophage infiltration of adipose tissue persisted, notably these cells were less pro-inflammatory, had lower CXCL1 production, and consequently, lower neutrophil chemoattraction into the tissue. These findings reveal macrophage NOD1 as a cell-specific target to combat diet-induced inflammation past the step of macrophage infiltration, leading to insulin resistance.
View details for DOI 10.1016/j.celrep.2017.02.027
View details for PubMedID 28273456
The common mouse protozoa Tritrichomonas muris alters mucosal T cell homeostasis and colitis susceptibility.
The Journal of experimental medicine
2016; 213 (13): 2841–50
The mammalian gastrointestinal tract hosts a diverse community of microbes including bacteria, fungi, protozoa, helminths, and viruses. Through coevolution, mammals and these microbes have developed a symbiosis that is sustained through the host's continuous sensing of microbial factors and the generation of a tolerant or pro-inflammatory response. While analyzing T cell-driven colitis in nonlittermate mouse strains, we serendipitously identified that a nongenetic transmissible factor dramatically increased disease susceptibility. We identified the protozoan Tritrichomonas muris as the disease-exacerbating element. Furthermore, experimental colonization with T. muris induced an elevated Th1 response in the cecum of naive wild-type mice and accelerated colitis in Rag1-/- mice after T cell transfer. Overall, we describe a novel cross-kingdom interaction within the murine gut that alters immune cell homeostasis and disease susceptibility. This example of unpredicted microbial priming of the immune response highlights the importance of studying trans-kingdom interactions and serves as a stark reminder of the importance of using littermate controls in all mouse research.
View details for DOI 10.1084/jem.20161776
View details for PubMedID 27836928
View details for PubMedCentralID PMC5154950
Discrete TCR Binding Kinetics Control Invariant NKT Cell Selection and Central Priming.
Journal of immunology (Baltimore, Md. : 1950)
2016; 197 (10): 3959–69
Invariant NKT (iNKT) cells develop and differentiate in the thymus, segregating into iNKT1/2/17 subsets akin to Th1/2/17 classical CD4+ T cells; however, iNKT TCRs recognize Ags in a fundamentally different way. How the biophysical parameters of iNKT TCRs influence signal strength in vivo and how such signals affect the development and differentiation of these cells are unknown. In this study, we manipulated TCRs in vivo to generate clonotypic iNKT cells using TCR retrogenic chimeras. We report that the biophysical properties of CD1d-lipid-TCR interactions differentially impacted the development and effector differentiation of iNKT cells. Whereas selection efficiency strongly correlated with TCR avidity, TCR signaling, cell-cell conjugate formation, and iNKT effector differentiation correlated with the half-life of CD1d-lipid-TCR interactions. TCR binding properties, however, did not modulate Ag-induced iNKT cytokine production. Our work establishes that discrete TCR interaction kinetics influence iNKT cell development and central priming.
View details for DOI 10.4049/jimmunol.1601382
View details for PubMedID 27798168
Nod1 and Nod2 enhance TLR-mediated invariant NKT cell activation during bacterial infection.
Journal of immunology (Baltimore, Md. : 1950)
2013; 191 (11): 5646–54
Invariant NKT (iNKT) cells act at the crossroad between innate and adaptive immunity and are important players in the defense against microbial pathogens. iNKT cells can detect pathogens that trigger innate receptors (e.g., TLRs, Rig-I, Dectin-1) within APCs, with the consequential induction of CD1d-mediated Ag presentation and release of proinflammatory cytokines. We show that the cytosolic peptidoglycan-sensing receptors Nod1 and Nod2 are necessary for optimal IFN-γ production by iNKT cells, as well as NK cells. In the absence of Nod1 and Nod2, iNKT cells had a blunted IFN-γ response following infection by Salmonella enterica serovar Typhimurium and Listeria monocytogenes. For Gram-negative bacteria, we reveal a synergy between Nod1/2 and TLR4 in dendritic cells that potentiates IL-12 production and, ultimately, activates iNKT cells. These findings suggest that multiple innate pathways can cooperate to regulate iNKT cell activation during bacterial infection.
View details for DOI 10.4049/jimmunol.1301412
View details for PubMedID 24163408
CD155 on human vascular endothelial cells attenuates the acquisition of effector functions in CD8 T cells.
Arteriosclerosis, thrombosis, and vascular biology
2011; 31 (5): 1177–84
CD155 is a cell surface protein that has recently been described to exert immune regulatory functions. We have characterized the expression of CD155 on human vascular endothelial cells (ECs) and examined its role in the regulation of T-cell activation.CD155 was expressed on resting human vascular ECs and was upregulated in an interferon-γ (IFNγ)-dependent manner. When the function of CD155 in regulating T-cell activation was examined, antibody-mediated neutralization of CD155 did not affect CD8 T-cell proliferation in response to stimulation with ECs. However, neutralization of CD155 activity or small interfering RNA-mediated inhibition of CD155 expression in ECs increased expression of IFNγ and cytotoxic effector function in activated CD8 T cells.CD155 is an IFNγ-inducible immune regulatory protein on the surface of human ECs that attenuates the acquisition of effector functions in CD8 T cells.
View details for DOI 10.1161/ATVBAHA.111.224162
View details for PubMedID 21330602
Inflammatory cytokines determine the susceptibility of human CD8 T cells to Fas-mediated activation-induced cell death through modulation of FasL and c-FLIP(S) expression.
The Journal of biological chemistry
2011; 286 (24): 21137–44
The nature of inflammatory signals determines the outcome of T cell responses. However, little is known about how inflammatory cytokines provided to human CD8 T cells during activation affects their susceptibility to post-activation cell death. We have examined and compared the effects of the inflammatory cytokine IL-12, as well as the combination of IL-1, IL-6, and IL-23 (IL-1/6/23) on the susceptibility of primary human CD8 T cells to post-activation cell death. Human CD8 T cells activated in the presence of IL-1/6/23 underwent significantly less cell death after activation as compared with those activated in IL-12. This was due to reduced susceptibility to Fas-mediated activation-induced cell death (AICD). Mechanistically, the reduced level of cell death in CD8 T cells activated in IL-1/6/23 was a result of a low level of FasL expression and high level of c-FLIP(S) expression. When the effect of IL-1, IL-6, and IL-23 individually was examined, IL-1 or IL-6 alone was sufficient to inhibit CD8 T cell death that occurs after activation in IL-12. IL-1, but not IL-6, inhibited expression of FasL, whereas IL-6, but not IL-1, increased c-FLIP(S) expression. Our findings show that the presence of IL-1 and/or IL-6 during activation of human CD8 T cells attenuates Fas-mediated AICD, whereas IL-12 increases the susceptibility of activated CD8 T cells to this form of cell death.
View details for DOI 10.1074/jbc.M110.197657
View details for PubMedID 21518761
View details for PubMedCentralID PMC3122175