Australian researchers at the Walter and Eliza Hall Institute (WEHI) have found that a genetic change that increases the risk of inflammation, through a process described as ‘explosive’ cell death, is carried by up to 3% of the global population.
The study, published this week in Nature Communications, may explain why some people have an increased chance of developing conditions like inflammatory bowel disease or suffer more severe reactions to infections with bacteria like Salmonella.
MLKL is a gene essential to triggering necroptotic cell death – a natural process that protects against infection, but in some people this process can go awry and trigger severe tissue damage.
Lead author, WEHI’s Dr Sarah Garnish, said that while there were various types of cell death, necroptosis was distinguished by its ferocity – the cells essentially explode, which sounds an alarm for other cells in the body to respond.
“Necroptosis is a caspase independent form of programmed cell death induced by danger- or pathogen-associated molecular patterns that signal via transmembrane receptors or intracellular pattern recognition receptors, which originated as a defence against pathogens,” she explained.
“In mouse studies, MLKL-mediated cell death has been implicated as a driver or suppressor of diseases spanning almost all physiological systems depending on the pathological context.
“However, being highly inflammatory in nature, necroptosis can also result in the permeabilization of biological membranes and the release of cytokines, nucleic acids, and intracellular proteins into the extracellular space.”
The S132P polymorphism is the third most frequent human MLKL missense coding variant in the gnomAD database and to examine its potential human disease-causing effects, the researchers exogenously expressed MLKLS132P in human cell lines and introduced the mouse counterpart variant (MlklS131P) into a genetically modified mouse model.
“What we revealed was that this polymorphism confers MLKL gain-of-function in a cell- and stimulus-dependent manner” Dr Garnish said.
“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.
“However, some of us make a form of MLKL with flimsy brakes – uncontrolled or excessive necroptosis can actually trigger disease.”
The team quantified the impact of these suicide cells at a population level for the first time and project leader, Dr Joanne Hildebrand, said their findings highlighted the impact of polygenic risk interacting with a person’s lifestyle and infection history to increase the risk of inflammatory diseases and severe reactions to infections.
“Taking Type 2 diabetes as an example, it’s rare that just one gene change determines whether someone will develop the condition,” Dr Hildebrand said.
“Instead, many different genes play a role, as do environmental factors, like diet and smoking. And while 2-3% doesn’t seem like much, when you consider the global population, this adds up to many millions of people carrying a copy of the MLKL gene variant.”
She noted that while the team had not yet linked the variant with the chance of someone developing a specific condition, they saw “real potential for it to combine with other gene variants, and other environmental cues, to influence the intensity of our inflammatory response.”
“Our understanding of MLKL has come a long way since it surfaced by chance in a WEHI lab more than 20 years ago. Today’s research opens the door for future tests and screening to determine disease risks,” Dr Hildebrand said.
“This MLKL gain-of-function manifests in in vivo changes to the immune response, impaired bacterial clearance, and defective emergency haematopoiesis. These observed phenotypes provide important insights into how this highly frequent human MLKL S132P polymorphism may contribute to the progression of complex disease.
“Genome sequencing is becoming cheaper and more readily accessible and as more genomic data becomes available to researchers, it increases the likelihood that they can link common genetic variants, like the one described for MLKL, with disease.”
The researchers hope to pinpoint the genetic changes that might mean someone is more likely to have a severe case of COVID, or less likely to bounce back after chemotherapy.
“Every piece of information like this helps us make personalised medicine more of a reality,” Dr Garnish said.
The WEHI team is also investigating whether uncontrolled necroptosis could be beneficial in some circumstances, such as whether 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,” Dr Garnish said.
“We’re looking at the downsides of having this gene change, but we’re looking for the upsides as well. Intriguingly, we show that in the presence of NSA human MLKLS132P protein displays a gain-of-function that results in non-inhibitable cell death…
“Sepsis, where emergency haematopoiesis is an essential determinant in survival, is an interesting and highly evolutionarily important avenue of exploration for the study of MLKL S132P polymorphism frequency.”