A little-understood link between insulin resistance in cells and obesity could hold the key to improving immune responses against COVID-19 and other viruses, according to U of A researcher Sue Tsai.
"We hypothesize that insulin resistance in immune cells such as B cells is a major link between obesity and an impaired antiviral response, leading to increased disease severity and associated mortality," said Tsai, an assistant professor of medical microbiology and immunology in the Faculty of Medicine & Dentistry and Canada Research Chair in Immunometabolism/Diabetes.
Tsai received $830,026 to investigate the possible link. It's one of 22 new U of A projects to receive a total of $14.7 million in funding from the Canadian Institutes of Health Research.
There is a known correlation between high body mass index, an indicator of obesity, and how sick people get during a respiratory infection. But the mechanism behind it is not clear.
"During the H1N1 pandemic in 2009, obesity emerged as the leading risk for severe disease requiring hospitalization," said Tsai, who is a member of the Alberta Diabetes Institute, the Li Ka Shing Institute of Virology and the Women and Children's Health Research Institute.
"Right now, again, obesity and Type 2 diabetes are becoming leading risk factors for severe COVID-19."
Unlocking a mystery
Insulin resistance is a metabolic abnormality that is prevalent in aged and obese individuals. It can lead to high blood glucose and Type 2 diabetes.
"All cells of the body, except for the red blood cells, have an insulin receptor," she said. "We know what it does in metabolic tissue such as the adipose tissues, the liver and muscles, but we don't understand what it does to the immune system."
The Tsai team made an intriguing discovery that B cells — white blood cells that produce antibodies when the body is fighting a virus — can develop insulin resistance during diet-induced obesity. Now the researchers will explore the role of insulin in regulating immune response and how it is altered during obesity, using animals that have been modified to lack insulin receptors in their B cells.
The quantity and quality of antibodies produced by B cells can affect not only the immediate response to viral exposure but also future protection, Tsai said, because B cells acquire immunological memory. Once they've experienced an infection or been prompted by a vaccine to produce antibodies, they are primed to fight quickly when they see the same infectious agent again.
Obesity has been correlated with a weakened immune response to vaccines against influenza, hepatitis B and tetanus, she noted, and may also be responsible for the dysregulation of the immune system in some people with COVID-19.
Tsai and her research team will examine how the B cells metabolize glucose, amino and fatty acids as fuel, and will observe whether administering calorie-restricted diets or diabetes medications can boost B cell responses.
The project will be carried out with a number of collaborators, including Caroline Richard, a nutrition and immunology researcher in the Faculty of Agricultural, Life and Environmental Sciences; Matthew Macauley, a B cell glycoimmunology researcher in the Faculty of Science; the U of A's Metabolomics Innovation Centre; and Igor Jurisica, a computational biologist at the University Health Network.
CIHR-funded projects at the U of A
Geoff Ball, Faculty of Medicine & Dentistry, Josephine Ho, Alberta Children's Hospital Research Institute, and Ian Zenlea, Trillium Health Partners
Attrition in pediatric obesity management: A randomized feasibility study
$462,825
Khaled Barakat, Faculty of Pharmacy and Pharmaceutical Sciences
Investigating the cell-based activity of a new class of cytotoxic T-lymphocyte antigen-4 (CTLA-4) small molecule inhibitors
$508,726
Amit Bhavsar, Faculty of Medicine & Dentistry
Advancing the therapeutic opportunity for TLR4 in reducing cisplatin-induced ototoxicity
$956,250
Stephane Bourque, Faculty of Medicine & Dentistry
Targeting renal vascular and mitochondrial dysfunction to prevent acute kidney injury in sepsis
$830,026
Valerie Carson, Faculty of Kinesiology, Sport, and Recreation, and Sandra Wiebe, Faculty of Arts
Screen technology, parent-child interactions, and neurocognitive development in early childhood
$436,051
Carole Estabrooks and Greta Cummings, Faculty of Nursing
How missed care occurs in nursing homes: A qualitative study of care aides' perspectives
$206,550
Dean Eurich, School of Public Health, and Bonnie Healy, Siksikaitsitapi Blackfoot Confederacy Tribal Council
Influence of the COVID-19 pandemic on chronic disease management among First Nations people in Alberta
$420,750
Edan Foley, Faculty of Medicine & Dentistry
Characterizing the effects of immune activity on intestinal epithelial regeneration during a Vibrio cholerae infection
$826,200
Rene Jacobs, Faculty of Agricultural, Life and Environmental Sciences
Dietary ethanolamine and phosphoethanolamine phosphorylase (ETNPPL) as novel modulators of liver health
$688,500
Satyabrata Kar, Faculty of Medicine & Dentistry
Biodegradable acidic nanoparticles attenuate beta-amyloid aggregation/toxicity: potential implication in the treatment of Alzheimer's disease pathology
$730,576
Padma Kaul, Kevin Bainey and Roopinder Sandhu, Faculty of Medicine & Dentistry, and Russ Greiner and Abram Hindle, Faculty of Science
The EXamining Population-Level mORtality from the Electrocardiogram using Artificial Intelligence (EXPLORE-AI) Study
$596,700
Harley Kurata, Faculty of Medicine & Dentistry
Multi-protein architecture of voltage-gated potassium channel complexes
$810,900
Paul LaPointe, Faculty of Medicine & Dentistry
Investigating the regulation of the Hsp90 functional cycle by ATP, co-chaperones, and post-translational modifications
$1,048,050
Afsaneh Lavasanifar, Faculty of Pharmacy and Pharmaceutical Sciences
Targeted delivery of novel inhibitors of DNA repair and combination treatments for the modulation of therapeutic response against metastatic colorectal cancer
$654,075
Gavin Oudit, Faculty of Medicine & Dentistry
Role of angiotensin converting enzyme 2 in cardiovascular complications due to metabolic disorders
$833,850
Qiumin Tan, Faculty of Medicine & Dentistry
Neuronal demise in the developing brain shapes the adult brain
$776,476
Anna Taylor, Faculty of Medicine & Dentistry
Central amygdala inflammation and chronic pain
$799,426
Richard Thompson and Amy Kirkham, Faculty of Medicine & Dentistry, and Mark Haykowsky, Faculty of Nursing
Quantitative imaging of the evolution of the whole-body fat profile in breast cancer survivors
$755,440
Sue Tsai, Faculty of Medicine & Dentistry
B cell-intrinsic insulin resistance as a mechanism of obesity-linked immune dysfunction
$830,026
Larry Unsworth, Faculty of Engineering
Peptide decorated magnetic nanoparticle strategies for minimally invasive targeting and removing exfoliation materials from the anterior lens capsule
$589,050
John Ussher, Faculty of Pharmacy and Pharmaceutical Sciences
Discovery and development of brain-sparing inhibitors of succinyl-CoA:3-ketoacid CoA transferase
$898,876
Dawei Zhang, Faculty of Medicine & Dentistry
Dissecting the role and underlying mechanism of Surf4 in regulating lipid metabolism
$830,026
