What the research is about
Shigellosis is an infectious disease that causes severe abdominal pain, diarrhea, and bloody stools. The disease is caused by Shigella bacteria, which invade cells lining the intestine and multiply inside them.
Normally, our bodies are protected by the immune system, which detects and eliminates invading microbes such as bacteria. The reason Shigellacan still cause disease is that it has the ability to survive-and even win-the battle against our immune defenses.
When the immune system detects pathogens, it activates inflammation and can force infected cells to undergo programmed cell death in order to stop the spread of infection. Two major forms of this defense are apoptosis and necroptosis, both of which are built-in mechanisms that allow cells to sacrifice themselves for the protection of the body. Previous studies have shown that Shigella uses a syringe-like structure called the type-III secretion system to inject proteins known as effectors into host cells. These effectors interfere with immune responses in highly sophisticated ways.
More recently, scientists have discovered that the immune system is even more advanced than previously thought. It can sense not only invading bacteria themselves, but also the interference caused by bacterial effectors. This powerful countermeasure is known as effector-triggered immunity.
Given such advanced immune defenses, how does Shigella still succeed in establishing infection? A research team led by Associate Professor Hiroshi Ashida and Professor Toshihiko Suzuki at Institute of Science Tokyo (Science Tokyo) set out to uncover how Shigella breaks through this final line of immune defense.
Why this matters
The team made a world-first discovery: Shigella disables the immune system's ultimate weapon-cell death-through a three-step strategy.
(1) Suppressing inflammation
Shigella first uses an effector protein called OspI to weaken inflammatory responses, allowing the bacteria to multiply inside the cell. However, this abnormal interference is detected by the host cell, which then triggers apoptosis to eliminate both itself and the invading bacteria.
(2) Blocking apoptosis
To counter this, Shigella deploys another effector, OspC1, which directly inhibits caspase-8, a key molecule that determines whether a cell proceeds toward apoptosis.
This action, however, activates a new alarm: the cell switches to an even more aggressive form of cell death known as necroptosis.
(3) Shutting down necroptosis
Finally, Shigella uses a third effector, OspD3, to block the signaling pathway of necroptosis itself. In this way, the bacterium successively overrides each layer of the cell's defense system.
Each time one defense is breached, another is activated-and Shigella overcomes them one by one. The researchers revealed the full picture of this remarkably precise survival strategy, showing how the bacterium anticipates and outmaneuvers the immune system.
What's next
This study reveals, at the molecular level, how Shigella "reads" the immune system and avoids its attacks. By understanding the role of each effector protein in detail, researchers can now identify vulnerabilities in the bacteria that were previously hidden.
These findings are expected to contribute not only to the development of new treatments for shigellosis, but also to a deeper understanding of-and better strategies against-other bacterial infections.
Unraveling this battle of wits between bacteria and the human body will be an essential foundation for preparing for future, as-yet-unknown infectious diseases.
Comment from the researchers
Bacteria are far too small to see with the naked eye, yet they establish infections using astonishingly sophisticated strategies.
I believe that uncovering these strategies is the first step toward science that truly protects human health. For anyone who wants to deeply understand how life works, this is an extremely rewarding field of research.
（Hiroshi Ashida, Associate Professor, Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo）
（Toshihiko Suzuki, Professor, Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo）
