Results of MI4 Pfizer Early Career Investigator Award

Winners

Year 2

MI4 is pleased to award funding for two investigators in Year 2 of the MI4 Pfizer Early Career Investigator Award program. MI4 would like to acknowledge that support for this program has been provided by Pfizer Canada Inc.

MI4 is also delighted to announce that they have partnered with the McGill University Faculty of Medicine and Health Sciences to support an additional project, with a gift from the Charles O. Monat Foundation, for the FMHS-MI4 Early Career Investigator Award.

Please join us in congratulating the following researchers on their successful submissions.

Lead Investigator

MI4 Pfizer Early Career Investigator Award

Qian Liu

PhD (McGill)

Single-molecule interactions between Nipah virus and the interferon-induced transmembrane proteins

Lay Summary

Viral infections pose a great threat to public health and the global economy. The majority are caused by emerging viruses that originated from animals and infect humans. It is urgent to develop intervention strategies against emerging viral diseases. We need to understand the fundamental mechanisms of how viruses infect cells and how the cell's innate immune defenses against the novel viral infections. Nipah virus (NiV) is an emerging paramyxovirus with the capability of human-human and animal-human transmissions and has a mortality rate of 40-70%. It is listed in the WHO blueprint priority diseases for research and development because of its epidemic potential and lack of countermeasures. Like other Enveloped viruses, NiV enters cells via the fusion between the virus and cell membranes. The interferon-induced transmembrane proteins (IFITMs) restrict the entry of unrelated viruses by modulating the biophysical properties of the membrane. Here, by using a combination of single-molecule imaging, mutagenesis, and biochemistry tools, we will probe how IFITMs restrict the entry and transmission of the NiV on a nanoscale. The precise information on the nano organization of viral and host factors will provide new insights into the subtle mechanisms of NiV infection and IFITMs’ antiviral activities.

Laurence Chapuy

MD, PhD (MUHC)

Plasticity of human monocytes towards regulatory macrophages in Crohn's disease

Lay Summary

Inflammatory bowel disease (IBD), including Crohn's disease (CD), affects 300,000 Canadians. IBD is caused by an abnormal immune response resulting in chronic intestinal inflammation that can lead to gut scarring, called fibrosis. This scarring results in a narrowing of the intestine that may require one or more surgeries during the course of the disease. Dr. Chapuy's research program focuses on the role of immune cells called monocytes and macrophages in developing intestinal fibrosis. When blood monocytes enter the intestine, they transform into macrophages, which will promote inflammation, tissue repair, or fibrosis, depending on the context. This ability of monocytes to adapt to the environment is called cell plasticity. We study the characteristics of monocytes and macrophages in the fibrotic intestine of CD patients who underwent surgery. Using state-of-the-art technologies, we analyze surgical specimens to define the nature and function of different cell types present in the scarred and adjacent healthy areas. By comparing them, we can deduce if and how the different types of monocytes and macrophages in the intestine promote fibrosis. The project aims to develop drugs to treat or prevent complications in CD patients and improve long-term outcomes and quality of life.

Lead Investigator

FMHS-MI4 Early Career Investigator Award, with a gift from the Charles O. Monat Foundation 

Ajitha Thanabalasuriar

PhD (McGill)

Deciphering the mechanism of e-cigarette mediate development of lung disease

Lay Summary

Electronic cigarettes (e-cigs) were originally introduced to help adults stop smoking tobacco. However, the use of sweet and fruity flavours has resulted in e-cigs becoming increasingly popular among teenagers (12-18 years old). Teens that have been using e-cigs for less than one year have been reported to develop rapid and life-threatening lung disease. Lung disease seen in e-cig using teenagers include lung injury and pneumonia. Improper immune responses to lung infections, ranging from scarce to excess immune cells moving into the lung, can result in disease. We have developed a mouse model of e-cig vape usage with one of the most popular ecig vape flavours (berry mix) and devices among teenage users. Using this model, we have found that e-cig vape containing a berry flavor decreases the important infection fighting immune cell, neutrophils, in the body. In this proposal we will understand what causes this change in neutrophil numbers and how e-cig exposed animals respond to infection. Moreover, we will look at human e-cig users to see if they have similar changes in neutrophils in their blood. Together we aim to understand and prevent lung disease after e-cig use.

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Year 1

MI4 is pleased to award funding for two investigators in Year 1 of the MI4 Pfizer Early Career Investigator Award program. MI4 would like to acknowledge that support for this program has been provided by Pfizer Canada Inc.

MI4 is also delighted to announce that they have partnered with the LDI and JGH Foundation to support an additional project for the LDI-JGH MI4 Early Career Investigator Award. Congratulations to all the awardees!

Please join us in congratulating the following researchers on their successful submissions.

Lead Investigator

MI4 Pfizer Early Career Investigator Award

Ian Watson

PhD (McGill)

Investigation of sex differences in response to immune checkpoint inhibitors in melanoma

Lay Summary

More men develop melanoma than women. Once male patients have melanoma, they have a worse prognosis than female patients. In the past, this has been attributed to differences in behavior. However, evidence now clearly points to biological sex differences being responsible for this phenomenon. Furthermore, reports are emerging that male and female patients have different drug responses to the latest melanoma treatments. Interestingly, reports indicate men have better responses to immune therapies and women respond better to targeted therapies. The reason for this is unknown.

Our group recently identified a gene that is preferentially mutated in male melanoma patients. We believe mutations in this gene may explain the observed sex differences in patient response to immune therapies, which we will investigate in this this study. Our research will lead to a better understanding of the differences in the biology of melanomas between male and female patients. Importantly, our study will work towards developing clinical tests that may help select patients most likely to benefit from either immune or targeted therapies.

Abhinav Sharma

MD (MUHC)

Optimizing the timing of influenza vaccination in patients with heart failure: the FLU-HF randomized trial

Lay Summary

Heart failure (HF) is one of the most common causes of hospital admission in Canada and costs the Canadian healthcare system over $1 billion annually. Influenza vaccination is an inexpensive strategy to prevent influenza infections and reduce an important trigger for HF decompensation and hospital readmission. Yet, the optimal timing of vaccine administration remains unclear. When patients with HF are admitted to the hospital with an acute decompensation in advance of, or during, the ‘flu season’, this can be an ideal time to administer the vaccine. However, patients with acute HF decompensation have significant inflammatory injury, and may have substantially impaired immune responses; thus vaccine administration while admitted during an acute decompensated HF episode may not lead to high anti-influenza antibody titres. A more effective strategy can be to vaccinate after the decompensation has resolved, when patients are more stable. The FLU-HF randomized trial will determine whether administering the influenza vaccine to patients admitted in-hospital with an acute HF decompensation or waiting until they have stabilized as an out-patient leads to an improved anti-influenza response. We hypothesize that the seasonal influenza vaccination given to patients acutely decompensated with HF will elicit diminished humoral immune response (seroresponse) compared to patients receiving vaccination when stabilized as an out-patient. The primary outcome will be the number of individuals who develop protective antibodies to influenza virus strains included in the vaccine. This study will significantly inform a larger multicentre trial evaluating clinical outcomes.

LEAD INVESTIGATOR

LDI-JGH MI4 EARLY CAREER INVESTIGATOR AWARD

Khashayar Esfahani

MD (JGH)

Uncoupling the efficacy and toxicity of immune checkpoint inhibitors through the novel use of kinase inhibitors

Lay Summary

In the last decade, cancer care has made enormous strides forward with the development of treatments that activate our natural immune system to attack cancer cells. Specifically, drugs called “Immune checkpoint inhibitors” (ICIs) have provided dramatic improvements in response and overall survival to a growing number of deadly malignancies. Unfortunately, the activated immune system does not always exclusively target cancer cells. Indeed, inappropriate targeting of normal human tissues has led to a wide variety of auto-immune side effects, which can sometimes be severe and long-lasting, even occasionally fatal.

We have studied how small molecules that inhibit intra-cellular signaling can modify the response to ICI in animal models, and more recently, in patients experiencing severe side effects. In this application, we propose to test whether such inhibitors can increase anti-tumor activity and/or decrease auto-immune toxicity in an animal cancer model where both anti-tumor activity and auto-immune toxicity are induced. Our focus will be on melanoma as the cancer model and immune colitis as the toxicity of interest. We anticipate this work to lead to the development of new treatments to combine with ICI to increase anti-cancer activity while decreasing or controlling immune side effects.

See the press release.

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