The study by Robert Schneider, Ph.D., the Albert B. Sabin Professor of Microbiology and Molecular Pathogenesis at NYU School of Medicine and his colleagues, is being published in the November 15th print edition of the journal Genes & Development
A killer and a protector
Septic shock is the nation's 10th most frequent cause of death and the leading cause of hospital-related mortality. Bacterial infection, notably the toxins that are part of the bacterial cell wall, stimulate the inflammatory response which can spin out of control. Sepsis progresses swiftly from chills, fever and shallow breathing, to dilated and leaky blood vessels, a lack of blood supply in the body's organs, multiple organ failure and, often, death.
Infection causes the body's immune system to produce protective proteins called cytokines. Problems arise when the body is unable to turn off cytokine production and they overwhelm the body, says Dr. Schneider. "The resulting cytokine storm is, for example, what kills people when they are infected with anthrax and, we think, an important factor in what killed people in the flu pandemic of 1918," he says.
Dr. Schneider and his colleagues focused on one of the key genes that regulate cytokine production called auf1, which has been extensively studied in tissue culture but not in animals. In an attempt to move the research closer to the clinical setting, the team genetically engineered and bred mice lacking the auf1 gene, a so-called knock-out mouse. Then, mice with the gene and mice without it were exposed to a bacterial toxin that causes mild food poisoning. The normal mice had little problem fending off the endotoxin. "The mice without the gene died due to an uncontrolled septic-shock like response--their blood vessels burst, their spleens were destroyed," says Dr. Schneider. Mortality was five-fold higher in mice without the auf1 gene.
Further research showed where auf1 functions at the molecular level, he says. In normal mice, the scientists found that auf1 steps into action once the immune response is activated and after cytokine production gets underway. The action is pronounced: messenger RNAs (mRNAs) which are blueprints for very specific cytokines--namely interleukin-1 beta, tumor necrosis factor alpha and COX-2--are degraded. That process of degrading the mRNAs shuts off production of these cytokines.
In the study, mice lacking the auf1 gene do not seem to have that off switch; their cytokine levels were greatly elevated. A cytokine storm had caused sepsis in these animals.
In summary, auf1 is a protector that can stop an infection from progressing to septic shock, explains Dr. Schneider. It does so by helping with cytokine production and then tempering the production of these proteins. Auf1 acts like a cytokine on/off switch.
The future possibilities
Dr. Schneider believes auf1 makes an excellent target for the development of therapeutics. For example, a drug could turn on auf1 or stabilize its activity as a way to specifically tone down production of those cytokines that are the major players in sepsis, he says. His study results might also help explain why many previous sepsis drug trials have failed. The cytokine storm needs to be turned off at its source, he says, and auf1 offers the on/off switch to do just that.
Jennifer Choi | EurekAlert!
The personality factor: How to foster the sharing of research data
06.09.2017 | ZBW – Leibniz-Informationszentrum Wirtschaft
Europe’s Demographic Future. Where the Regions Are Heading after a Decade of Crises
10.08.2017 | Berlin-Institut für Bevölkerung und Entwicklung
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
22.09.2017 | Life Sciences
22.09.2017 | Medical Engineering
22.09.2017 | Physics and Astronomy