Study uncovers the tradeoff between fast immune defense and long-term inflammation

Some of our biggest threats can come in the tiniest forms-viruses and bacteria. Thankfully, we are born with a built-in defense system, our innate immune system that protects us in our youth but can turn against us as we age. New research from the Stowers Institute for Medical Research is revealing why this tradeoff exists, identifying a common power source driving many immune system responses to pathogens. The findings may potentially lead to new ways to combat inflammation and diseases associated with aging like Alzheimer's, Parkinson's, and cancer.

From the lab of Associate Investigator Randal Halfmann, Ph.D., the study published in eLife on September 16, 2025, has revealed a common process that powers the creation of structured protein formations that assemble like a 3D puzzle. These protein "puzzles" help infected cells amplify invasion signals and destroy themselves, triggering inflammation that limits the spread of infection.

Like the striking of a match to produce a flame, our immune cells, which are found throughout our body, must undergo a large and irreversible response when encountering a tiny stimulus like a single molecule of viral DNA. Specific proteins within these cells that can quickly assemble are the death decision makers, and the process of their assembly is the decision for the cell to die. We are beginning to think that this may be one of the fundamental mechanisms of why we age." 

Randal Halfmann, Ph.D., Associate Investigator

A hallmark of these death-decision proteins is a "death fold domain" within their sequence that has the ability to assemble tightly together, but in such a complicated way that it almost never assembles accidentally. A piece of bacteria or virus getting into the cell provides a template to start the assembly.

"There are always more than enough of these proteins available to assemble in our cells, which allows the cell to rapidly respond to a threat," said Alex Rodríguez Gama, Ph.D., a former predoctoral researcher in the Halfmann Lab and lead author on the study. "This protein overpacking or 'supersaturation' is biology's equivalent of a battery, storing energy until it is needed to boost a signal that warns the body of an invasion, activating an immune response and inflammation." 

Our cells contain many different protein puzzles that can assemble when various pathogens are detected. Based on their previous work on one such protein assembly, the research team speculated that death-decision proteins may function more broadly as energy stores to drive their own assembly, which would otherwise take a lot of cellular energy. They tested their hypothesis by analyzing more than 100 human proteins with death fold domains using the tiniest of test tubes-single-celled yeast-and identified a subset with this battery-like property.

"A microscopic signal can tap into the battery's energy storage to suddenly form a very stable protein assembly and fight infection," said Rodríguez Gama.

While the surplus of proteins is a benefit to fighting infection quickly, the new research reveals a significant consequence. Sometimes these assemblies form on their own, without an invasion signal, simply due to random molecular fluctuations.

"As we age, it's inevitable that a death fold domain protein in a cell-if that cell lives long enough-will eventually change shape even in the absence of an invader, triggering protein assembly, cell death, and inflammation," said Halfmann. "It is a 'Catch 22.' Essentially, we are trading longevity for an immune system, or the greater certainty of life right now at the expense of potential longer life."

Inflammation plays a dual role-it offers immediate protection from infection but if it persists it can lead to chronic conditions. "Our findings provide insight into the mechanism of how inflammation can first start and what happens as we age, which can help us find new ways to address inflammation associated with infection and aging," said Rodríguez Gama.

"Inflammation is one of the major features of many of the diseases that are presently incurable-Alzheimer's, Parkinson's, most of the diseases associated with aging, and some cancers-but it starts within individual cells," said Halfmann.

"If we could reduce the probability of inflammation by perhaps removing some of those puzzle pieces or reshaping them so they can't assemble, then we might be able to block the inevitability of inflammation, and with time, develop ways to decelerate some of these diseases," said Halfmann. "While slowing or stopping the puzzle assembly could possibly increase susceptibility to pathogens, perhaps some patients would be willing to accept that risk."