Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Dark Ages scourge enlightens modern struggle between man and microbes

Scientists discover how Yersinia pestis avoids setting off immune system's early infection-alarm

The plague-causing bacteria Yersinia pestis evades detection and establishes a stronghold without setting off the body's early alarms.

Yersinia (gray) infects two macrophages. In the upper right pyroptosis was subverted via YopM, in the bottom left, pyroptosis is induced and an inflammasome is formed (white).

Credit: Brad Cookson lab

New discoveries reported this week help explain how the stealthy agent of Black Death avoids tripping a self-destruct mechanism inside germ-destroying cells.

The authors of the study, appearing in the Dec. 13 issue of Cell Host & Microbe, are Dr. Christopher N. LaRock of the University of Washington Department of Microbiology and Dr. Brad Cookson, UW professor of microbiology and laboratory medicine.

Normally, certain defender cells are programmed to burst if they are either invaded by or detect the presence of pathogens, Cookson explained. This host defense mechanism called pyroptosis ("going up in flames") eliminates places for the germs to reproduce. As it splits open, the cell spills a cauldron of antimicrobial chemicals and emits signals to alert of an attack and its precise location. Tissues become inflamed as more cells arrive to fight the infection.

The bacteria are widely believed to be behind the great pestilences of the Middle Ages in the 1300s. The pathogen had evolved a tactic to delay provoking people's protective inflammatory response until it was too late. Plague claimed an estimated 30 percent to 50 percent of Europe's 14th century population.

"People and pathogens have been in an eternal struggle since the dawn of humanity," Cookson said. With a hand over hand gesture he explained, "Humans continuously ratchet up their defenses, and germs repeatedly find a way around them."

During several medieval epidemics, the plague started in rats. High-jumping fleas transmitted it to and between humans. It commonly caused lymph nodes to rupture. Respiratory forms were more deadly. They damaged the lungs and were spread by sneezing. Plague bacteria in the blood stream ended lives through sepsis, in which the burden of infection overwhelms the body.

Today, the plague-causing bacteria are still circulating in the world. It is held at bay by sanitation measures and drug treatment.

Plague is now rare, with fewer than 15 infections annually in the United States. The number of cases outside the United States is significantly larger, but not precisely known. Plague therefore remains of scientific interest for several reasons.

The Yersinia survival strategy against the programmed death that could kill it and its host cell may offer ideas for vaccine development, Cookson said. At present, no vaccine exists against the plague. Yesinia is of concern as a potential biological warfare pathogen because it can be aerosolized and unsuspectingly breathed into the lungs. Vaccines are being sought to offer widespread public safety, as are methods for enhancing people's overall infection-fighting capacity.

Yersinia's techniques for modulating an inflammatory response also offer scientists an overarching perspective on a fundamental aspect of a variety of important diseases.

"Many medical problems stem from too much or too little inflammatory reaction," Cookson said. People who launch an insufficient inflammatory response, or whose inflammatory response is suppressed by medications, are prone to viral, bacterial and fungal infections.

"On the other hand, excessive or improperly regulated inflammatory responses are responsible for a large number of chronic conditions," Cookson said. These include vascular flare-ups leading to stroke or heart attack, and autoimmune diseases, among them lupus, juvenile diabetes, ulcerative colitis and myasthenia gravis. Severe injury also can promote life-threatening lung inflammation.

Additionally, plague isn't the only pathogen to enhance its virulence by sidestepping the inflammatory cell death program. Several other dangerous germs do the same, but in different ways.

Usually immune system clean-up cells that have been breached by an infection assemble a molecular platform called an inflammasome. This assembly, the researchers explained, activates a powerful, protein-cleaving enzyme called caspase-1. The enzyme is made ready to go in the presence of noxious stimuli, including germs, inorganic irritants, and pore-forming toxins.

To survive, Yersinia pestis must disarm caspase-1. Until the present study, bacterial molecules that directly modulate the inflammasome had not yet been reported. LaRock and Cookson were able to identify a leucine-rich protein secreted by Yersinia pestis that binds and disables its arch-enemy, the caspase-1 enzyme.

The potent substance, called Yop M, preempts the activity of caspase-1 and sequesters the enzyme to arrest the development of the inflammasome. As a consequence, the cell fails to sacrifice itself to get rid of the Yersinia and to warn other disease-fighting cells of the infection.

According to the researchers, the Yop M-mediated inhibition of caspase-1 is required for Yersinia to subvert immune signaling, delay inflammation and provoke severe illness. Its dual mechanism for blocking inflammatory cell death, by blocking enzymatic activity and inflammasome maturation, is distinctive.

While caspase-1 is helpful in combating a number of other microbial infections, several researchers have reported it to be harmful when its activation is aberrant or poorly controlled. Faulty caspase-1 regulation is implicated in several inflammatory disorders. Learning how pathogens manage caspase-1 to their advantage may suggest treatments to limiting its excess activity.

The research was funding by National Institutes of Health research grants HG02360 and AI057141 and National Institute of Health training grant AI055396. The study also received assistance from the Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases, which seeks countermeasures against pathogens of national importance.

The Dec. 13 Cell Host & Microbe paper is "The Yersinia Virulence Effector YopM Binds Caspase-1 to Arrest Inflammasome Assembly and Processing."

Leila Gray | EurekAlert!
Further information:

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Reliable in-line inspections of high-strength automotive body parts within seconds

Nondestructive material testing (NDT) is a fast and effective way to analyze the quality of a product during the manufacturing process. Because defective materials can lead to malfunctioning finished products, NDT is an essential quality assurance measure, especially in the manufacture of safety-critical components such as automotive B-pillars. NDT examines the quality without damaging the component or modifying the surface of the material. At this year's Blechexpo trade fair in Stuttgart, Fraunhofer IZFP will have an exhibit that demonstrates the nondestructive testing of high-strength automotive body parts using 3MA. The measurement results are available in a matter of seconds.

To minimize vehicle weight and fuel consumption while providing the highest level of crash safety, automotive bodies are reinforced with elements made from...

Im Focus: Kick-off for a new era of precision astronomy

The MICADO camera, a first light instrument for the European Extremely Large Telescope (E-ELT), has entered a new phase in the project: by agreeing to a Memorandum of Understanding, the partners in Germany, France, the Netherlands, Austria, and Italy, have all confirmed their participation. Following this milestone, the project's transition into its preliminary design phase was approved at a kick-off meeting held in Vienna. Two weeks earlier, on September 18, the consortium and the European Southern Observatory (ESO), which is building the telescope, have signed the corresponding collaboration agreement.

As the first dedicated camera for the E-ELT, MICADO will equip the giant telescope with a capability for diffraction-limited imaging at near-infrared...

Im Focus: Locusts at the wheel: University of Graz investigates collision detector inspired by insect eyes

Self-driving cars will be on our streets in the foreseeable future. In Graz, research is currently dedicated to an innovative driver assistance system that takes over control if there is a danger of collision. It was nature that inspired Dr Manfred Hartbauer from the Institute of Zoology at the University of Graz: in dangerous traffic situations, migratory locusts react around ten times faster than humans. Working together with an interdisciplinary team, Hartbauer is investigating an affordable collision detector that is equipped with artificial locust eyes and can recognise potential crashes in time, during both day and night.

Inspired by insects

Im Focus: Physicists shrink particle accelerator

Prototype demonstrates feasibility of building terahertz accelerators

An interdisciplinary team of researchers has built the first prototype of a miniature particle accelerator that uses terahertz radiation instead of radio...

Im Focus: Simple detection of magnetic skyrmions

New physical effect: researchers discover a change of electrical resistance in magnetic whirls

At present, tiny magnetic whirls – so called skyrmions – are discussed as promising candidates for bits in future robust and compact data storage devices. At...

All Focus news of the innovation-report >>>



Event News

EHFG 2015: Securing healthcare and sustainably strengthening healthcare systems

01.10.2015 | Event News

Conference in Brussels: Tracking and Tracing the Smallest Marine Life Forms

30.09.2015 | Event News

World Alzheimer`s Day – Professor Willnow: Clearer Insights into the Development of the Disease

17.09.2015 | Event News

Latest News

Unexpected information about Earth's climate history from Yellow River sediment

09.10.2015 | Earth Sciences

Single atom alloy platinum-copper catalysts cut costs, boost green technology

09.10.2015 | Life Sciences

Indefatigable Hearing

09.10.2015 | Life Sciences

More VideoLinks >>>