In a groundbreaking study, researchers have uncovered a unique genetic variation that may significantly influence how the immune system of First Nations people responds to infections. This research, part of an extensive eight-year project co-led by the Peter Doherty Institute for Infection and Immunity and Monash University, aims to shed light on the immune challenges faced by Indigenous populations, particularly in the context of severe respiratory viral diseases.
First Nations people, including Aboriginal and Torres Strait Islander communities, are disproportionately affected by severe respiratory viral infections such as COVID-19, pandemic influenza, and seasonal flu. While social determinants of health play a crucial role in this vulnerability, emerging evidence suggests that genetic variations within immune cells may also contribute significantly to the heightened risk. Understanding these genetic factors is essential for developing targeted health interventions.
Natural killer (NK) cells are a vital component of the body’s immune defense, acting as the first line of defense against viral infections. These cells can restrict viral replication during the early stages of infection, either eliminating low-level infections or providing critical time for the immune system to generate a more specific response. Consequently, the functionality of NK cells is pivotal in determining an individual’s ability to prevent infections and recover from viral illnesses.
A Deep Dive into Natural Killer Cells
The research team, which included experts from the Menzies School of Health Research, the University of Colorado, and Stanford University, focused on mapping a specific component of NK cells in First Nations populations. Professor Katherine Kedzierska from the University of Melbourne, who has been co-leading the research since 2016, emphasized the importance of understanding killer cell immunoglobulin-like receptors (KIRs) in these communities. These receptors are crucial for directing immune responses following viral infections.
One of the key findings of the study was the examination of a highly variable NK cell receptor known as KIR3DL1. This receptor exists in over 200 different forms in humans and is capable of binding to specific human leukocyte antigen (HLA) molecules. These HLA molecules play a critical role in presenting viral peptides to immune cells, and their variability can significantly impact immune responses.
Dr. Camilla Faoro, a co-first author of the study from Monash University, utilized advanced techniques at the Australian Synchrotron to gain detailed structural insights into how KIR3DL1 interacts with HLA molecules prevalent in Oceania. “Our research demonstrated that the Indigenous and Māori forms of KIR3DL1 bind more tightly to these common HLA molecules, enhancing the NK cells’ ability to sense and respond to infections,” Faoro explained.
Identifying Genetic Variants
A particularly intriguing aspect of the study was the identification of an ancient variant of the natural killer receptor that appears to be exclusive to the people of Oceania. This variant binds more strongly to HLA variants common among Oceanic populations, which could have significant implications for susceptibility to infections. Kedzierska noted that their analysis of over 1,300 individuals revealed that the frequency of this Oceanic variant was as high as 28% among highland Papuans and around 6% in First Nations people from Northern Australia.
This discovery underscores a critical point: genetic and immunological studies often overlook First Nations and other minority populations. “Our findings highlight the necessity of inclusively working with First Nations peoples. The insights gained from this research may inform the design of new vaccines and immunotherapies, ensuring they are effective across diverse populations,” Kedzierska stated.
Addressing Health Disparities
Professor Andrew Brooks, Head of the Natural Killer Cell Laboratory at the Doherty Institute and a co-senior author of the paper, emphasized the importance of understanding genetic differences in immune responses. “The extent to which NK cells can respond to viral infections and cancer is dictated by these highly variable genes, which are among the most diverse in the human genome,” Brooks explained.
He further elaborated that recognizing these genetic differences is crucial for addressing and reducing health disparities. “Understanding this diversity not only helps explain why responses to viral infections vary among individuals but also aids in identifying populations at higher risk of severe disease,” he added.
As this research continues to unfold, it holds promise for developing more effective health strategies tailored to the unique genetic makeup of First Nations peoples and other Indigenous populations worldwide.