Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Protein that fights bacteria and viruses cloned by Scripps scientists

21.07.2003


Bacteria and viruses are completely different classes of pathogens, and not surprisingly the body uses completely different molecular "receptors" to detect them in order to mount an immune defense.



Paradoxically, while the detection systems are different, the actual immune defenses the body employs to clear the system of viral or bacterial infection are much the same. As are the symptoms--to you or me, fighting off bacteria or viruses can produce the same fatigue, inflammation, or hacking cough.

Now a team of researchers at The Scripps Research Institute (TSRI) has published a paper appearing in an upcoming issue of the journal Nature that explains how pathogens as different as viruses and bacteria can have such a common bottom line.


"The proximal reason [for these similar symptoms] is a single protein," says TSRI Professor Bruce Beutler, M.D., who led the research.

This protein, called Trif, associates with different "receptors" that detect a virus or a bacterium on the surfaces of human cells. Trif is a signal transducer--it helps turn these positive detections into immune reactions. Significantly, Trif is the topmost protein shared by the pathway that detects gram-negative bacteria and the pathway that detects most viruses. It is like a waiter who brings orders from two different customers into the same kitchen.

This is the first time that anyone has identified a protein that directly responds to the signals the innate immune system sends when it recognizes both bacteria and viruses.

In addition, Trif could be a potential target for intervening in diseases in which the innate immune system plays a role, such as sepsis. Sepsis basically results from a runaway cascade of inflammation in response to a bacterial infection, and Trif is involved very early in this cascade. If drugs might be designed that could modulate the function of Trif, they might help to improve the prognosis for sepsis.

"You could imagine that blocking this pathway would have a pretty strong anti-inflammatory effect in a diverse range of infectious diseases," says Beutler, who identified and cloned the Trif gene (called Lps2) together with Kasper Hoebe, Ph.D., a postdoctoral fellow in the Beutler laboratory. TSRI Associate Professor Jiahuai Han, Ph.D. and Sung Kim, Ph.D., a postdoctoral fellow in Han’s laboratory, collaborated in this effort.

Mapping the Gene

Beutler, Hoebe, and their colleagues mapped the mouse gene Lps2, which has an equivalent gene in humans, after they found a deleterious mutation in a mouse gene that made mouse macrophages unable to sense certain pathogens, thus weakening their innate immune systems.

"Mice that lack this protein are very susceptible to infections like mouse cytomegalovirus," says Beutler, adding that the mice are also unable to respond to bacterial endotoxins, like lipopolysaccharide (LPS) molecules, which are found in the cell walls of many bacteria. In mammals, the innate immune system detects LPS and a multiplicity of other foreign molecules with a family of receptors called the toll-like receptors (TLRs). Mammals have 10 or more different TLR receptors, and one of the goals of scientists like Beutler is to identify how these receptors mediate innate immunity.

Innate immunity is essential for survival in a world filled with microbial pathogens because cells of the innate immune system are the body’s first responders, arriving soon after foreign pathogens are detected.

Normally, when human or mouse cells encounter bacteria or viruses, they recognize them with the help of TLRs and other proteins such as Trif. This recognition triggers the immune system, which responds with a multi-stage biochemical defense.

The first stage typically involves the innate immune system and its army of white blood cells, like macrophages, which engulf and destroy pathogens. The macrophages also fight the pathogens by producing chemicals at the site of an infection that induce inflammation. One of these chemicals is called tumor necrosis factor alpha (TNF-alpha). Normally, TNF-alpha is produced in great amounts by macrophages when they are exposed to bacterial and viral "ligands"--the molecules found in the cell walls of bacteria, for instance.

Beutler and his colleagues were able to identify the function of Trif and clone the Lps2 gene after they first observed how a random mutation in one mouse rendered its macrophages unable to produce TNF-alpha when exposed to LPS from gram-negative bacteria like E. coli or when exposed to double-stranded RNA--a product of many viral infections. LPS is known to signal via TLR4: a discovery made by TSRI investigators Beutler and Alexander Poltorak, Ph.D., several years ago. Double-stranded RNA signals via TLR3--another member of the family. For this reason, Beutler and his coworkers guessed that the mutation might affect a molecule required for both TLR3 and TLR4 to signal properly.

They mapped the Lps2 mutation to a 216,000-base pair region of chromosome 17. Of the eight genes in that region, one gene, then called Trif, was a prime candidate because it encoded an adaptor "TIR domain" protein--just the type of protein that might participate in signaling from toll-like receptors.

Beutler and his colleagues sequenced all of the genes in this region and found a mutation affecting a single nucleotide in the Trif (Lps2)gene. The mutation is a "frameshift" error--the 24 amino acids at the tail end of the gene are exchanged for a completely different set, and when the protein is translated in the cell, it cannot function.

The fact that macrophages with these malfunctioning Trif proteins did not respond to LPS suggests that Trif might make a good target for treating sepsis, which can occur during a widespread bacterial infection. During such an infection, macrophages produce inflammatory chemicals, which help to kill the bacterial cells. But if the systemic endotoxin levels are too high, the macrophages respond by producing a lethal amount of inflammatory chemicals.

Having a way to stop this would be a boon, because the current prognosis for sepsis is dire. It can affect many parts of the body, including the liver, kidneys, heart, intestines, adrenal glands and brain, and death due to septic shock can occur in a matter of hours. According to the Centers for Disease Control and Prevention, sepsis is one of the ten leading causes of both infant and adult mortality in the United States, and, in 1999, directly caused more than 30,000 deaths.

Another interesting conclusion found in the paper is that macrophages with no Trif protein can be divided into two different populations--one pool of cells that are slightly responsive to LPS, and one pool that are unresponsive. This is important because scientists have long considered macrophages to be a homogeneous population of cells.

After observing this, Beutler and his colleagues discovered that even normal macrophages fall into different pools that can be distinguished on the basis of how well they respond to certain stimuli. The apparent heterogeneity might suggest that macrophages specialize somewhat in their function.

"I would guess that some macrophages are better at killing virus-infected cells than at coping with bacteria [and vice-versa]," says Beutler.

The article, "Identification of Lps2 as a key transducer of MyD88-independent TIR signaling" was authored by Kasper Hoebe, Xin Du, Philippe Georgel, Edith Janssen, Koichi Tabeta, Sung Ouk Kim, Jason Goode, Pei Lin, Navjiwan Mann, Suzanne Mudd, Karine Crozat, Sosathya Sovath, Jiahuai Han, and Bruce Beutler and appears in the Advance Online Publication feature of the journal Nature on July 20, 2003.

Jason Bardi | EurekAlert!
Further information:
http://www.nature.com/nature
http://www.scripps.edu

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Supersensitive through quantum entanglement

28.06.2017 | Physics and Astronomy

X-ray photoelectron spectroscopy under real ambient pressure conditions

28.06.2017 | Physics and Astronomy

Mice provide insight into genetics of autism spectrum disorders

28.06.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>