Like a poisoned feather, dying cells prick their neighbors with a lethal message. This can make sepsis worse, Vijay Rathinam and colleagues at UConn School of Medicine reported in the Jan. 23 issue of Cell. Their findings could lead to a new understanding of this dangerous disease.
Sepsis is one of the most common causes of death worldwide, according to the World Health Organization (WHO), killing 11 million people each year. It is characterized by uncontrolled inflammation, usually caused by an infection. It can cause shock, multiple organ failure, and death if treatment is not quick or effective enough.
But recent research has shown that it’s not actually the infection that causes spiral inflammation: it’s the cells trapped in it. Even if those cells are not infected, they act as if they are and die. When they die, they send messages to other cells. Those messages somehow cause the recipient cells to die. If scientists understood what caused this chain of deadly messages, they could stop it. And that could help cure sepsis.
The mystery of the deadly message can now be solved. It appears that the “messages” are a byproduct of cells trying to stay alive, UConn School of Medicine researchers report in Cell.
The process begins with cells that are actually infected. To prevent the infection from spreading, these cells are destroyed by sending a protein called gasdermin-D to their surface. Several gasdermin-D proteins will join together to create a round pore in the cell, like a hole punched in a balloon. The contents of the cell leak, the cell collapses and dies.
But collapse is not inevitable. Sometimes cells can act quickly and expel the section of their surface membrane with the gasdermin-D pore. The cell then closes the membrane and survives. The expelled membrane forms a small bubble, called a vesicle, which turns out to contain the deadly gasdermin-D pore. The vesicle floats, and when it encounters a nearby cell, that deadly gasdermin-D pore punctures the membrane of the nearby healthy cell, causing that cell to spill over and die.
“When a dying cell releases these vesicles, it can transplant these pores to the surface of a neighboring cell, causing the death of the neighboring cell,” says Vijay Rathinam, an immunologist at the University of Connecticut School of Medicine. In other words, the deadly messages are a side effect of cells simply trying to save themselves. A group of dying cells can release enough gasdermin-D vesicles to kill a considerable number of nearby cells. This message of death that is spread feeds the spiral of inflammation of sepsis.
Rathinam and his colleagues are now looking for a way to dampen the deadly gasdermin-D vesicles. If successful, it could lead to a treatment for inflammatory diseases such as sepsis.
This study led by Skylar Wright, a PhD student in Rathinam’s lab, was conducted in collaboration with the laboratories of Drs. Jianbin Ruan, Beiyan Zhou, Sivapriya Kailasan Vanaja of UConn Health, and Dr. Katia Cosentino of Osnabrück University, Germany. This project was funded by grants from the National Institutes of Health to Dr. Rathinam.