Dr. Angela M. Crawley

Biography

Highlights of Research Interests

Human CD8 T cell function, macrophage subset differentiation, chronic liver disease (chronic hepatitis C virus infection, non-alcoholic fatty liver disease), advanced liver fibrosis/cirrhosis, animal models of liver fibrosis, hepatocellular carcinoma, immune phenotyping, inflammatory biomarker assessment, immune restorative therapies, translational immunology research

Research Interests

Chronic liver disease can take a toll on the body’s immune system, both in the liver itself, and systemically. This can pose challenges for individuals experiencing advanced liver disease or cirrhosis, due to viral or metabolic mechanisms. These effects can be somewhat long-lasting, despite any potential resolution or control of the hepatic infection or mitigation or ongoing liver damage. As a result, individuals can be at risk for adverse clinical outcomes such as impaired immune responses to infections, immunization and ongoing risk for hepatocellular carcinoma. Central to this, is the adequate functioning of CD8 T cells, important immune cells in responses to viral infections and cancer. The Crawley laboratory is endeavoring to identify the underlying mechanisms of lasting CD8 T cell hyperfunction in advanced liver fibrosis/cirrhosis, with a focus on chronic hepatitis C virus infection and non-alcoholic fatty liver disease. To do this, the research program spans research topics in human immunology and animal models, designed with a translation research intention. A strong team of basic science and clinical research collaborators supports this research program. The Crawley lab also maintains a large biobank to store clinical research samples for this program and ongoing collaborative research activities.

1. CD8 T cell dysfunction in chronic HCV infection with advanced liver fibrosis

Funded by: Canadian Institutes of Health Research Project Grant

Despite the spectacular results for hepatitis C virus (HCV) clearance with new antiviral therapies, significant challenges remain for those with advanced liver fibrosis/cirrhosis. Progressive fibrosis results in symptomatic liver disease, predisposing to end-stage liver disease with a high mortality. Although antiviral therapy reduces the risk of liver cancer, cirrhotic patients remain at risk, and data suggests an atypically aggressive form can occur. Weakened responses to routine vaccinations and co-infections and chronicity with HCV re-exposure demonstrate the consequences of an immune system weakened by cirrhosis. Given that the majority of the 175 million HCV cases worldwide become chronic infections, with most remaining undiagnosed and only a fraction of known infections being treated annually, studies estimate the number of HCV+ individuals with cirrhosis will remain high for decades.

An immune cell profoundly affected by chronic HCV infection is the CD8 T cell. Effective CD8 T cell responses are not only vital for viral clearance but are central to cancer surveillance and responses to other viral infections and increasingly important for vaccines in development against chronic viral infections requiring robust T cell immunity. We have found significant CD8 T cell dysfunction in cirrhotic HCV-infected individuals that persists long after cure, and suspect similar dysfunction in non-infectious liver disease. We are using gene sequencing methods to identify the underlying mechanism and are already following up on promising candidates. We are also using a mouse model emulating liver disease and CD8 T cell dysfunction, performing elegant mechanistic studies to complement our human research. These mice are clinically relevant with impaired responses to both cancer and immunotherapy, as is seen in humans. Our research will identify new immunorestorative therapeutic targets to improve clinical outcomes for cirrhotic HCV+ individuals and other liver diseases.

2. The mechanisms by which circulating macrophages and their liver counterparts (Kupffer cells) alter CD8+ T-cell activity

Funded by: Natural Sciences and Engineering Research Council Discovery Grant

The orchestration of T-cell responses by innate immune cells such as macrophages is a hallmark of adaptive immunity as they establish inflammatory, immunoregulatory or tissue-repairing molecular milieus. The direct and indirect effects of macrophage subsets on CD8+ T-cell cytolytic (CTL) functions, which are critical for anti-viral or anti-tumoural responses, remain unclear. Specifically, the influence of tissue-specific macrophage subsets in the liver, such as Kupffer cells (KC) and hepatic stellate cells (HSC), on CD8+ T-cells is not understood. In the liver, these macrophages maintain immune tolerance in health and balance immune response and tissue destructive effects in liver disease. We hypothesize that the inherent pro- and anti-inflammatory attributes of blood monocyte-derived macrophage subsets and equivalently derived subsets of KC and HSC will enhance or inhibit CTL function. This research will complement our research program which studies the effects of liver disease on CTL function in the context of hepatitis C virus (HCV) infection and HIV-HCV co-infection in which we have observed significant impairment of CD8+ T-cells, indicating widespread immune dysfunction that may be relevant to other diseases causing liver fibrosis. Improvement of industrial yeast strains used in cellulosic fermentation

3. The use of animal models to study liver fibrosis and CD8 T cell dysfunction and the effects on cancer development

Funded by: Canadian Institutes of Health Research Project Grant

We are also using a mouse liver fibrosis model with similar CD8 T cell dysfunction, performing elegant mechanistic studies with ectopic and liver cancer challenges to complement our human research. There is significant translational potential to clinically relevant issues of cancer and immunotherapy in humans with liver disease, as we see rapid tumor growth and a delayed response to immunotherapy in mice with liver disease. We will identify immunorestorative therapeutic targets to improve clinical outcomes in liver disease.

Are you interested in joining the Crawley Lab for your graduate or postdoctoral training?  Please send your CV to [email protected]

Select Publications

• Odai KG., O’Dwyer C., Steenbergen R., Shaw T., Renner T., Ghorbani P., Langlois M-A., Crawley AM., Russell RS., Pezacki J., Tyrrell LD., Fullerton MD. In vitro hepatitis C virus infection and hepatic choline metabolism. Viruses, 12(1). pii: E108, 2020.
• Vranjkovic A., Deonarine F., Angel JB., Cooper CL., Crawley AM. Dysfunction of bulk circulating CD8⁺ T-cells in chronic HCV infection is associated with liver disease severity and is unresolved after HCV cure. Frontiers Immunol., 10:1926, 2019.
• Doyle MA., Lee T., Singer J., Crawley AM., Klein M., Cooper CL. Evaluation of safety and effectiveness of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Switch followed by Ledipasvir-Sofosbuvir HCV Therapy in HIV-HCV Co-Infection. Open Forum Infectious Diseases 6(7). pii: ofz318 2019.
• Ahmed F., Ibrahim A., Cooper CL., Kumar A., Crawley AM. Macrophage subsets are dysfunctional in chronic HCV infection and contribute to CD8+ T-cell impairment. Cells 2019, 8:374 - Special Issue: Hepatitis C Virus and Host Interactions, by invitation.
• Doyle M-A., Mulvihill E., Galanakis C., Crawley AM., Cooper CL. Influence of Ribavirin and the Cirrhotic State on Metabolic Measures in Hepatitis C Direct Acting Antiviral Treatment Recipients. Cells 2019, 8:252 -Special Issue: Hepatitis C Virus and Host Interactions, by invitation.
• Khan S., Bernier, A., Dapp D., Fortier E., Krajden M., King A., Grebely J., Sagan SM., Cooper CL., Crawley AM. 6th Canadian Symposium on HCV: Delivering a Cure for Hepatitis C Infection: What are the Remaining Gaps? Can. Liver J. 2018, Vol 1(2):94-105.
• Khan S., Karges W., Cooper C., Crawley AM. Hepatitis C virus core protein reduces CD8⁺ T-cell proliferation, perforin production and degranulation but increases STAT5 activation. Immunol. 2018 154(1):156-65.
• Steele (Leone) A.K., Carrasco-Medina L., Sodora D.L., Crawley AM. Increase in soluble IL-7 receptor levels in plasma is associated with improved therapeutic outcome to IL-7 therapy in SIV-infected ART-treated Rhesus macaques. PlosOne 2017, 12(12): e0188427.
• Corsi DJ., Karges W., Thavorn K., Crawley AM., Cooper CL. Influence of female sex on hepatitis C virus infection progression and treatment outcomes. European Journal of Gastroenterology and Hepatology. 2016 28(4): 405-411.
• Burke SC., Carrasco-Medina L., Karges W., Cooper CL., Crawley, AM. Generalized liver- and blood-derived CD8⁺ T cell impairment in response to cytokines in chronic hepatitis C virus infection. PlosOne. 2016 11(6): e0157055.
• Côté, S., Matte, J., Sad, S., Angel, JB, Crawley AM. Complexed soluble IL-7 receptor α and IL-7 increase IL-7-mediated proliferation and viability of CD8+ T-cells in vitro. Cell. Immunol. 2015 293(2):122-125.
• Crawley AM., Vranjkovic A., Faller E., McGuinty M., Burke SC., Cousineau S., MacPherson P., Angel JB. Jak/STAT and PI3K signalling pathways have both common and distinct roles in IL-7 mediated activities in human CD8⁺ T-cells. J. Leuk. Biol., 2014. 95(1):117-27.
• Crawley AM., and Angel JB. 2012. The influence of HIV on CD127 expression and its potential implications for IL-7 therapy. (Invited review article for Semin. Immunol., 24:231-240.
• Vranjkovic A., Crawley AM., Patey A., Angel JB. 2012. In vitro HIV Type 1 infection indirectly alters CD127 expression on CD8⁺ T-cells. AIDS Research and Human Retrovirology. 28:295-298.
• Crawley AM., and Angel JB. 2011. Expression of g-chain cytokine receptors on CD8⁺ T-cells in HIV infection with a focus on IL-7Ra (CD127). Immunol. Cell. Biol. 90:379-387.
• Vranjkovic A., Crawley AM., Patey A., Angel JB. 2011. IL-7-dependent STAT-5 activation and CD8⁺ T-cell proliferation are impaired in HIV infection. J. Leuk. Biol., 89:499-506. Note: An editorial introduces this article in its issue: Paiardini M. et al., 2011. J. Leuk Biol. 89:491-3.
• O’Connor A., Crawley AM., Angel JB. 2010. The role of IL-7 in memory CD8⁺CD127⁺ T-cell function and its impairment in HIV disease. Immunol., 131(4):525-536.
• Crawley AM., Vranjkovic A., Young C., Angel JB. 2010. Interleukin-4 downregulates CD127 expression on human thymocytes and mature CD8⁺ T-cells. Eur. J. Immunol., 40:1396-1407.
• Crawley, AM., Faucher S., Angel JB. 2010. Soluble IL-7Ra (sCD127) inhibits IL-7 activity and is increased in HIV infection. J. Immunol., 184:4679-4787.
• Faucher S., Crawley AM., Decker W., Sherring A., Bogdanovic D., Ding T., Bergeron M., Angel JB., Sandstrom P. 2009. Development of a Quantitative Bead Capture Assay for Soluble IL-7 Receptor a in Human Plasma. PLoSONE, 4(8): e6690.
• Crawley AM., Katz T., Parato KP., Angel JB. 2009. IL-2 receptor g chain cytokines differentially regulate human CD8⁺CD127⁺ and CD8⁺CD127^- T-cell division and susceptibility to apoptosis. Int. Immunol., 21: 29-42.
• Vranjkovic A.^*, Crawley AM.^* Gee K., Kumar A., Angel JB. 2007. IL-7 decreases IL-7 receptor- α (CD127) expression and induces shedding of CD127 by human CD8⁺ T cells. Int. Immunol., 19: 1329-1339. (*contributed equally).