Passion for discovery
“Discoveries are the joy of my life,” says Dr. Shokrollah Elahi, an immunologist in the Faculty of Medicine and Dentistry, University of Alberta. “Curiosity is part of me. It’s in my blood, my genes. I’ve always wanted to explore and discover things. It’s probably the foundation of my career.”
As an 11-year-old Iranian middle-school student, Elahi pulverized leftover medication, put it in a suspension and injected it into stray lizards to see how they would react. His innate curiosity led him to pursue a medical degree at the University of Tehran, Iran, then a PhD in immunology in Australia.
“I realized that my passion was discovery, and I wanted to do something that would have a global impact.”
During his career, Elahi has made substantial discoveries that have contributed to our knowledge of HIV infection and transmission, our understanding of how the newborn immune system works, and more.
His current studies focus on three areas of interest: HIV pathogenesis, particularly the biological mechanisms of natural immunity; how and why neonates develop infections; and what’s behind immune cell exhaustion in chronic viral infections and cancer.
The road to discovery
After earning his PhD, Elahi decided to pursue a postdoctoral fellowship at the Vaccine and Infectious Diseases Organization (VIDO) in Saskatoon, Sask. While there, he developed a novel porcine model for whopping cough, which he later used to show how maternal prenatal vaccination protects newborns against the disease. During this time, he began to wonder why newborns are so susceptible to infection.
He then pursued a second postdoctoral fellowship at the University of Washington in Seattle. There, he first encountered the natural phenomenon of HIV resistance. Long-term non-progressors (LTNPs) represent less than 1% of HIV-infected individuals. Healthy and symptom-free, they have normal CD4 counts, low viral levels and no need for antiretroviral therapy.
“My project was to try to understand the mechanism and discover why these individuals are naturally resistant to HIV infection at the cellular and molecular levels.”
In 2011, his findings were published in Nature Medicine. In this subset of HIV-infected individuals, he found that CD8 T cells (killer T cells) in the immune system resist exhaustion. Specifically, they possess certain HLA alleles, HLAs B27 and B57, which suppress TIM-3, an inhibitory receptor (immune checkpoint). Higher levels of TIM-3 shut down the immune response. By suppressing TIM-3, the immune system of HIV-resistant individuals can continue to fight HIV infection.
Elahi then moved to Cincinnati Children’s Hospital Medical Center in Ohio to answer a question that had haunted him since VIDO. Why are newborns more susceptible to infections than adults?
At the time, the prevailing belief was that newborns had an underdeveloped immune system. “We see that newborns can’t talk, walk, make a decision or operate an iPhone 7,” he jokes. “So, we assume that their immune system is dysfunctional.”
Elahi’s preliminary work at VIDO had contradicted this concept. In Ohio, his research led to a landmark discovery, published in Nature.
“We challenged the old notion of neonatal immune system immaturity,” he explains. “In essence, we highlighted active immune suppression in place.”
In studies of mice and human cord blood, he and his group of researchers found that a newborn’s immune system is fully functional, but the neonatal environment is actively immunosuppressive.
Physiological abundance of immature red blood cells (CD71 cells) in newborns actively suppresses their immune system. These cells are absent in healthy human adults, he explains.
“We discovered that immunosuppression is essential at the earliest stages of life in order to allow a swift adaptation to good bacteria in the gut and on the skin,” he explains.
When the fetus starts its journey down the birth canal, it is exposed to millions of germs, some of which become part of the body’s micobiome. If the immune system were to fight this kind of bacterial colonization, he says, it would result in inflammation in the gut and will be detrimental to its health in later life.
Diverse research interests
Since arriving at the University of Alberta, Elahi has continued to study how the immune system develops in newborns. He recently traveled to Uganda, where his group will examine the role of immature red blood cells in mother-to-child HIV transmission. He and a collaborator have established a longitudinal study to investigate their role in inflammatory bowel disease (IBD).
In 2017, he and his coworkers discovered that prenatal maternal vaccination passes antibodies and cytokines to newborns, both of which are essential for immunity. Passive cytokine transmission may impact immune cell differentiation in newborns. The team published another two articles on how the immature red blood cells influence the innate and adaptive immunity in newborns in the Journal of Immunology and Scientific Reports.
Elahi has actively recruited HIV-resistant individuals in Alberta, collecting billions of cells for genetic and molecular testing. His goal is to understand why their immune cells do not express the immune checkpoint TIM-3 but instead express granzyme B, which kills viral or tumour cells. This work may lead to the development of new vaccines or other therapies.
It also has links to another research interest: immune cell exhaustion. In chronic viral infections and cancer, killer T cells stop working. They become “exhausted”. When dysfunctional, they express immune checkpoints like TIM-3. Elahi and his group plan to study the mechanisms of immune cell exhaustion in skin cancer (melanoma) as well as lymphoma and leukemia.
“My hope is that trying to understand T cell exhaustion and eventually reverse it,” he says. “The whole concept is to try to better understand the underlying mechanisms in order to invigorate the immune system to fight back and eliminate tumours or viral-infected cells.”
Current immunotherapies target only two of many immune checkpoints: CTLA-4 and PD-1. Elahi hopes to identify others to target with immunotherapy.
Puzzling it out
“We have to try our best to make a difference and understand how we can help someone, whether they are afflicted with an infectious disease or cancer,” says Elahi.
“There’s a big puzzle out there, and we’re just trying to solve it. We might do a piece of it, but it’s our job to do our best. One day, someone will put all of those pieces together that other scientists have discovered to solve the whole puzzle.”