The study 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.

At a glance

• MLKL is a gene essential to triggering necroptotic cell death — a natural process that protects our body from infection. In some people this process can go awry and trigger severe tissue damage.

• Study finds a genetic variation, known to enhance the ability of MLKL to kill cells, is carried by up to 3% of the global population.

• The findings could lead to better personalised treatments for inflammation and other diseases in the future.

Immune power of ‘explosive’ cell death

Every minute, millions of cells in our bodies die on purpose. Cell death is an essential process that protects our bodies from disease by removing unwanted, damaged or dangerous cells, and preventing the spread of viruses, bacteria, and even cancer.

WEHI’s Dr Sarah Garnish is first author on the paper and said that while there are various types of cell death, necroptosis is distinguished by its ferocity — the cells essentially explode, which sounds an alarm for other cells in the body to respond.

“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 actually trigger disease.”

Genetic brakes

The gatekeeper of necroptosis is the gene MLKL. When the body needs to trigger a cell death response with plenty of firepower, the cellular brakes that normally keep MLKL in-check are released. However, some of us make a form of MLKL with flimsy brakes.

Dr Garnish and her co-authors have been able to quantify this at a population level for the first time.

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

“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 this gene variant.”

Project leader Dr Joanne Hildebrand said the research proposes that a common genetic change like this can combine with a person’s lifestyle, infection history and broader genetic makeup to increase the risk of inflammatory diseases and severe reactions to infections.

This is known as polygenic risk — the combined influence of multiple genes on developing a certain trait or condition.

“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.”

Dr Hildebrand said it’s 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.”

Towards personalised medicine

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.

Genome sequencing is becoming cheaper and more readily accessible. 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.

In the future researchers hope to pinpoint the genetic changes that might mean someone is more likely to have a severe case of COVID-19, or less likely to bounce back after chemotherapy.

“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 beneficial in some 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.”

The research was supported by the National Health and Medical Research Council, the Victorian State Government, the Australian Government Research Training Program Stipend Scholarship and the Wendy Dowsett Scholarship.

WEHI authors: Sarah Garnish, Katherine Martin, Maria Kauppi, Victoria Jackson, Shene Chiou, Yanxiang Meng, Daniel Frank, Emma Tovey, Komal Patel, Annette Jacobsen, Georgia Atkin-Smith, Ladina Di Rago, Marcel Doerflinger, Christopher Horne, Cathrine Hall, Samuel Young, Ian Wicks, Ashley Ng, Charlotte Slade, Andre Samson, John Silke, James Murphy and Joanne Hildebrand.

Unequal interactions between cilia cause synchronization

To create a synchronized and efficient wave, cilia need to accurately coordinate their beating motion. Unlike football fans watching their neighbors and the nervous system coordinating the centipede’s legs, cilia have no such intelligent control system.

In their new study, the scientists David Hickey, Ramin Golestanian and Andrej Vilfan from the department Living Matter Physics at MPI-DS now highlight the importance or border regions for the coordination of cilia. “When many cilia beat closely together, they can synchronize by beating slightly before their neighbors to one side, and slightly after their neighbors to the other — just like a Mexican wave in a stadium,” says David Hickey, first author of the study. This synchronization is mediated by the fluid surrounding the cilia and initiated by the border region. Notably, two cilia beating near each other don’t necessarily exert the same force to each other. Depending on its position, a cilium can be more effected by its neighbor than vice versa, especially in a dense carpet of cilia as it frequently occurs in nature. This can eventually cause a directed, non-reciprocal pattern forming a wave.

Synchronization of cilia is initiated by border regions

“The cilia at a border region take the role as a pacemaker which entrain other cilia one after another,” Hickey summarizes the findings. “This observation is different from previous models where boundaries were assumed to perturb the order,” he continues. This view was also shared by the renowned physicist Wolfgang Pauli who joked about this: “God made solids, but surfaces were the work of the devil.”

As found now, border regions of surfaces can in fact allow a better understanding of the self-organization of living matter. At the same time, the model reveals striking similarities between mechanisms in the microscopic world and on the macroscopic scale.

A vortex is a rotating region of fluid, such as air or water, characterized by intense rotation. Common examples include typhoons and tornadoes frequently observed in news reports. Professor Choi’s mathematical proof establishes the stability of specific types of vortex structures that can be encountered in real-world fluid flows.

The study builds upon the foundational Euler equation formulated by Leonhard Euler in 1757 to describe the flow of eddy currents. In 1894, British mathematician M. Hill mathematically demonstrated that a ball-shaped vortex could maintain its shape indefinitely while moving along its axis.

Professor Choi’s research confirms that Hill’s spherical vortex maximizes kinetic energy under certain conditions through the application of variational methods. By incorporating functional analysis and partial differential equation theory from mathematical analysis, this study extends previous investigations on two-dimensional fluid flows to encompass three-dimensional fluid dynamics with axial symmetry conditions.

One notable feature identified by Hill is the presence of strong upward airflow at the front of the spherical vortex — an attribute often observed in phenomena like typhoons and tornadoes. Professor Choi’s findings serve as a starting point for further studies involving measurements related to residual time associated with these ascending air currents.

“Research on vortex stability has gained international attention,” stated Professor Choi. “[A]nd it holds long-term potential for advancements in today’s weather forecasting technology.”

Supported by funding from Korea Research Foundation under the Ministry of Science and ICT as well as UNIST, this study was published ahead of official release on July 24th via the online edition of Communications on Pure and Applied Mathematics.

Concerning reports about avian flu outbreaks at poultry facilities across the country and abroad highlight the increasingly urgent need for a safe and effective vaccine that could thwart a possible spread of the virus from human to human. To be ready to safely and efficiently test promising vaccine candidates, researchers developed an animal model that more closely mimics the typical symptoms of human infection than any such model so far. This proactive work minimizes the steps needed to quickly validate and deploy a new vaccine in a crisis.

“The COVID-19 pandemic got people to realize that it is not enough to respond to a pandemic when it happens. We really need to make sure that we are ready before it is here,” said co-senior author Doug Reed, Ph.D., associate professor of immunology at Pitt’s Center for Vaccine Research.

Bird flu, caused by H5N1 influenza virus, is primarily spread by migratory wild birds and can decimate poultry populations, including chickens and ducks. Although the virus has infected people, previous infections have not spread efficiently from human to human. However, there are documented cases of H5N1 spreading in mammalian populations, ranging from minks to sea lions and dolphins, raising concern about human-to-human spread.

People infected with H5N1 virus can develop acute respiratory distress syndrome, or ARDS, manifesting in short and labored breathing. H5N1 kills more than half of those infected.

To ensure that a future vaccine will be protective, the researchers turned to macaques, which have close anatomy and physiology to humans, making them a choice model for the testing of life-saving medicines.

Reed and his coauthor, Simon Barratt-Boyes, Ph.D., professor of infectious diseases and microbiology at the Pitt School of Public Health, reasoned that delivering H5N1 virus by small particle aerosol would make it more likely to reach deep into the lung and mimic natural exposure. They first demonstrated this aerosolized infection model in research published in 2017. In the new paper, they refined their model and evaluated whether a seasonal flu vaccine, which protects against human influenza A and B viruses, when given three times with an experimental adjuvant could prevent ARDS upon exposure to aerosolized H5N1 virus.

All monkeys that received adjuvanted seasonal flu vaccine were protected from death, and there were low but measurable neutralizing antibodies against H5N1 in their blood samples, the quantity of which was inversely correlated with the severity of their symptoms.

While the researchers caution that their findings do not mean that a seasonal flu vaccine can efficiently protect against bird flu, they are optimistic that protective efficacy of future vaccines that target H5N1 can be tested using this model and deployed faster.

“The original idea behind this work was more than 20 years in the making,” said Reed. “Now there is a path forward to get people protected against this devastating disease.”

Masaru Kanekiyo, Ph.D., of the NIH Vaccine Research Center, also contributed to the study.

The University of Pittsburgh has received funding support as an agreement under NIH contract number HHSN261201500003I to Leidos Biomedical Research in Frederick, Maryland.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.