WEHI researchers have found that a genetic change of MLKL increases risk of uncontrolled inflammatory response  

Published in Nature Communications, Australian researchers at the Walter and Eliza Hall Institute have discovered that 3 percent of the global population carries a genetic change that increases the risk of inflammation, by a process described as ‘explosive’ cell death.

The study could explain why some people have an increased chance of developing conditions like inflammatory bowel disease or suffer more severe reactions to bacterial infections.

‘Explosive’ cell death 

Cell death is an essential process that protects against disease by removing damaged or dangerous cells and preventing the spread of viruses, bacteria and cancer.

WEHI’s Dr Sarah Garnish said that compared to other types of cell death, necroptosis is distinguished by its power. The cells explode, which signals for other cells in the body to respond.

“But when necroptosis is uncontrolled or excessive, the inflammatory response can trigger disease.”

“This is a good thing in the case of a viral infection, where necroptosis not only kills the infected cells but instructs the immune system to respond, clean things up, and start a more specific, long lived immune response,” Dr Garnish said.

“But when necroptosis is uncontrolled or excessive, the inflammatory response can trigger disease.”

Genetic brakes

The gene MLKL is the gatekeeper of necroptosis.  When the body requires a powerful cell death response the cellular brakes that usually keep MLKL in-check release. However, some people make a form of MLKL with flimsy brakes.

“For most of us, MLKL will stop when the body tells it to stop, but 2–3 percent of people have a form of MLKL that is less responsive to stop signals,” Dr Garnish said.

“While 2-3 percent doesn’t seem like much, when you consider the global population, this adds up to many millions of people carrying a copy of this gene variant.”

Dr Joanne Hildebrand said the research points to polygenic risk, where a common genetic change like this can combine with a person’s lifestyle, infection history and broader genetic makeup which increases the risk of inflammatory diseases and severe reactions to infections. However, Dr Hildebrand said it is not as simple as directly connecting this difference in the MLKL gene with the chance of someone developing a specific condition.

“We haven’t tagged this MLKL gene variant to any one particular disease yet, but we see real potential for it to combine with other gene variants, and other environmental cues, to influence the intensity of our inflammatory response.”

Personalised medicine

The understanding of MLKL has dramatically increased since its chance discovery in a WEHI lab over 20 years ago. Today’s research prompts future tests and screening to determine disease risks.

Genome sequencing is becoming cheaper and more accessible. As more genomic data becomes available to researchers, it increases the likelihood of linking common genetic variants, like the one described for MLKL, with disease.

Researchers hope to determine the genetic changes that may mean someone is more likely to have a severe case of COVID-19 for example. “Every piece of information like this helps us make personalised medicine more of a reality,” said Dr Garnish.

The WEHI team is also investigating whether uncontrolled necroptosis could be helpful in certain circumstances. For example, could people with the MLKL gene variant have a stronger cellular defensive response to certain viruses?

“Gene changes like this don’t usually accumulate in the population over time unless there is a reason for it – they generally get passed on because they do something good,” said Dr Garnish.

“We’re looking at the downsides of having this gene change, but we’re looking for the upsides as well.”