How do infections and toxins launch a cell's self-destruct and alarm system?

March 10, 2008
Pyroptosis: How a Dying Cell Sounds an Alarm
This schematic shows the cell death pathway called pyroptosis, Greek for going down in flames. When activated by a toxin or an infection, the enzyme caspase-1 initiates several reactions inside of the cell, some of which lead to DNA damage, others to the release of chemical distress signals called cytokines, and others to the formation in the cell membrane of tiny pores that let water flood in until the cell swells, bursts and spills its contents. Image by David W. Ehlert and Brad Cookson, University of Washington

Cells are coded with several programs for self-destruction. Many cells die peacefully. Others cause a ruckus on their way out.

Some programmed cell death pathways simply and quietly remove unwanted cells, noted a team of University of Washington (UW) researchers who study the mechanisms of cell destruction.

Then there is the alarm-ringing death of a potentially dangerous cell, such as a cell infected with Salmonella, they added. These dying cells spill chemical signals and get a protective response. The resulting inflammation, which the body launches in self-defense, can at times backfire and damage vital tissues.

A research team lead by Dr. Brad T. Cookson, an associate professor of microbiology and laboratory medicine, named this type of cell death "pyroptosis," Greek for going down in flames. Cell death that doesn't cause inflammation is called "apoptosis": to drop gently like leaves from a tree.

An enzyme inside cells, called caspase-1, plays a critical role in both harmful inflammation and in resistance to infection, Cookson and his colleagues noted. It's not just responsible for cell death, but also for the production of inflammatory proteins that are released from the dying cell. Mice deficient in caspase-1 are susceptible to infection, yet resistant to toxic shock, tissue injury from lack of oxygen, and inflammatory bowel disease.

The Cookson lab has done many studies of caspase-1 and how it mediates the pathway of pro-inflammatory programmed cell death. The lab's most recent study will be published the week of March 10 to March 14 in the online Early Edition of the Proceedings of the National Academy of Sciences. The study looked at how two different noxious stimuli, anthrax toxin and Salmonella infection, trigger the caspase-1-mediated cell death pathway. UW graduate students Susan Fink and Tessa Bergsbaken conducted this study.

The researchers found that each of these stimuli took an independent route to activate caspase-1; however, these two distinct mechanisms of activation eventually converged on a common pathway of cell death. This common pathway featured cleavage of the cell's DNA, activation of inflammatory chemical messengers, and the final jettison of the cells contents. The spillage occurs after nano-scale pores form in the cell membrane, much like punctures in a water balloon.

According to Cookson, these findings are helping to create research models for studying a broadly important pathway of pro-inflammatory programmed cell death. The findings also support the notion that diverse disease agents can use different mechanisms to elicit this pathway.

"Examining this system provides insight into mechanisms of both beneficial and pathological cell death, and the strategies that infectious disease agents employ to manipulate the body's responses," Cookson said. His group's previous studies of Yersinia, the plague pathogen, revealed that cell death mechanisms can be re-directed from a passive, non-inflammatory pathway, to a more beneficial inflammatory pathway. This finding suggests the possibility of treating diseases by modulating cell death pathways.

"In addition to its protective role in fighting infection," Cookson added, "caspase-1 also plays a role in many medical conditions characterized by cell death and inflammation." These conditions include organ damage in the heart, brain, lungs, nerves, and kidneys. Understanding pro-inflammatory cell death pathways may lead to new therapies against fatal or disabling diseases, such as serious infections, heart attack, cancer and stroke.

Cookson is part of the National Institutes of Health-funded Microscale Life Sciences Center, a collaboration among scientists and engineers from the UW, the University of Arizona, the Fred Hutchinson Cancer Research Center, and Brandeis University. The scientists work to discover basic mechanisms in the formation, growth, and decline of human cells. Their aim is to develop biotechnology to combat widespread diseases and environmental threats to human health.

Source: University of Washington

Explore further: Genetic test identifies 'high risk' lymphatic cancer patients

Related Stories

Genetic test identifies 'high risk' lymphatic cancer patients

February 20, 2018
Around 1,500 people in Denmark are diagnosed with lymphatic cancer each year. A small sub-group (70 to 80 people) develop a rare and aggressive type of lymphatic cancer, known as mantle cell lymphoma (MCL).

IFN-mediated immunity to influenza A virus infection influenced by RIPK3 protein

February 15, 2018
Each year, influenza kills half a million people globally with the elderly and very young most often the victims. In fact, the Centers for Disease Control and Prevention reported 37 children have died in the United States ...

Researchers find a pathway that leads to resistance of aggressive brain tumor treatment

February 16, 2018
Glioblastoma multiforme is one of the most common and deadly brain tumors. Despite the initial responsiveness to state-of-the-art therapies, tumors virtually always become resistant and eventually recur. Researchers at Dartmouth's ...

Drug that treats psoriasis also reduces aortic vascular inflammation

February 16, 2018
An antibody used to treat the skin disease psoriasis is also effective at reducing aortic inflammation, a key marker of future risk of major cardiovascular events. Researchers from the Perelman School of Medicine at the University ...

Study maps molecular mechanisms crucial for new approach to heart disease therapy

February 13, 2018
Creating new healthy heart muscle cells within a patient's own ailing heart. This is how scientists hope to reverse heart disease one day. Today, a new study led by UNC-Chapel Hill researchers reveals key molecular details ...

Study suggests way to attack deadly, untreatable nerve tumors

February 12, 2018
Genomic profiling of mostly untreatable and deadly nerve sheath tumors led scientists to test a possible therapeutic strategy that inhibited tumor growth in lab tests on human tumor cells and mouse models, according to research ...

Recommended for you

Clues to obesity's roots found in brain's quality control process

February 20, 2018
Deep in the middle of our heads lies a tiny nub of nerve cells that play a key role in how hungry we feel, how much we eat, and how much weight we gain.

Study looks at how newly discovered gene helps grow blood vessels

February 19, 2018
A new study published today found that a newly discovered gene helps grow blood vessels when it senses inadequate blood flow to tissues.

Scientists produce human intestinal lining that re-creates living tissue inside organ-chip

February 16, 2018
Investigators have demonstrated how cells of a human intestinal lining created outside an individual's body mirror living tissue when placed inside microengineered Intestine-Chips, opening the door to personalized testing ...

Data wave hits health care

February 16, 2018
Technology used by Facebook, Google and Amazon to turn spoken language into text, recognize faces and target advertising could help doctors fight one of the deadliest infections in American hospitals.

Researcher explains how statistics, neuroscience improve anesthesiology

February 16, 2018
It's intuitive that anesthesia operates in the brain, but the standard protocol among anesthesiologists when monitoring and dosing patients during surgery is to rely on indirect signs of arousal like movement, and changes ...

Team reports progress in pursuit of sickle cell cure

February 16, 2018
Scientists have successfully used gene editing to repair 20 to 40 percent of stem and progenitor cells taken from the peripheral blood of patients with sickle cell disease, according to Rice University bioengineer Gang Bao.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.