Study offers clues on First Nations' susceptibility to infections

Researchers have uncovered a unique genetic variation that may influence how the immune system responds to infections.

As a part of an eight-year project, co-led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute) and Monash University, researchers comprehensively mapped a component of natural killer cells in First Nations people.

First Nations people globally, including Aboriginal and Torres Strait Islander people, are at high risk of severe respiratory viral diseases, including COVID-19, pandemic influenza and seasonal influenza. In addition to social determinants of health, genetic variations within immune cells may contribute to the increased risk.

Natural killer cells are part of the body’s first line of defence against viral intruders, which can restrict viruses from replicating in the earliest stages of infection. This is crucial because they can either eliminate low level infection completely or buy time for the generation of virus-specific immunity. Consequently, these immune cells play a key role in an individual’s ability to both prevent infection and recover from a virus.

Findings from this study, done in partnership with Menzies School of Health Research (Northern Territory), the University of Colorado and Stanford University, could guide the development of new vaccines and immunotherapies to ensure they work effectively across diverse populations.

A highly variable natural killer cell receptor

The University of Melbourne’s Professor Katherine Kedzierska, Head of the Human T Cell Laboratory at the Doherty Institute and co-senior author of the paper, has been co-leading the research since 2016.

“We focused our research on the origin, distribution and functions of killer cell immunoglobulin-like receptors in First Nations people, as these receptors are crucial components that direct immune responses following viral infections,” Kedzierska said.

Specifically, the study examined a highly variable natural killer cell receptor, called KIR3DL1, of which there are over 200 forms in humans, capable of binding to subsets of a person’s human leukocyte antigens (HLA) molecules, which present viral peptides for recognition by immune cells, and are themselves highly variable.

Dr Camilla Faoro, co-first author of the study from Monash University, used the Australian Synchrotron to provide detailed structural insights into the impact of killer cell immunoglobulin-like receptors found in First Nations Peoples at the molecular level.

“We have shown how the Indigenous and Māori forms of KIR3DL1 interact with the most common HLA molecules in Oceania, which explains why they bind more tightly than the KIR3DL1 forms predominant in other parts of the world,” Faoro said.

“This tighter binding changes the capacity of natural killer cells to sense and respond to infection.”

Reducing disparities in outcomes

Critically, the team identified an ancient variant of the natural killer receptor that appears to be exclusive to the people of Oceania, binding more strongly to the HLA variants that are common to Oceanic peoples, Kedzierska said.

“Our analyses of over 1300 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, which could influence susceptibility to infection,” she said.

She noted that genetic and immunological studies often do not involve First Nations and other minority populations around the world.

“Recent studies including this one, underscore the importance of inclusively working with First Nations peoples. Our learnings may inform the design of new vaccines or vaccine regimens and immunotherapies, helping to ensure these agents are effective for the broad sweep of human populations,” she said.

The University of Melbourne’s Professor Andrew Brooks, Head of the Natural Killer Cell Laboratory at the Doherty Institute and a co-senior author of the paper, said the extent to which natural killer cells can respond to viral infections and cancer is dictated by these genes, which are among the most variable in the human genome.

“At a global level, genetic differences contribute to population-specific immune variation, so gaining insights into these differences is important for both addressing and reducing disparities in health outcomes,” Brooks said.

“An understanding of this diversity is key not only to explain why responses to viral infections differ from person to person, but it may also allow us to identify individuals and/or populations at higher risk of severe disease.”

Image caption: iStock.com/Eoneren