Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

TSRI scientists show that rare genetic mutations increase susceptibility to sepsis

29.04.2003


A group of researchers from The Scripps Research Institute (TSRI) have discovered rare genetic mutations in a subset of people who come down with a particular kind of severe sepsis, an acute and often deadly disease.



These rare mutations in a human gene called TLR4 lend susceptibility to meningococcal sepsis, which strikes over 2,500 people a year in the United States. About half of those who contract meningococcal sepsis are younger than the age of two, and the disease has an overall case fatality rate of 12 percent.

"It’s a very fast-moving, dramatic, and often fatal disease," says TSRI Immunology Professor Bruce Beutler, who led the research, which will be published in an upcoming issue of the journal Proceedings of the National Academy of Sciences.


"We took a large number of people with meningococcal sepsis and compared them to normal controls who were ethnically and geographically matched," says Beutler. "We found that the TLR4 gene had more mutations in the sepsis populations."

Besides demonstrating that the risk of severe sepsis increases with these mutations, which can be passed from parent to child, the study also suggests that it may be possible to protect people who are at risk. While not practical at the moment, eventually patients with mutations to their TLR4 genes might be given prophylactic treatment, for instance, before they undergo surgery or travel somewhere they are likely to be exposed to meningococcal bacteria.

Blinding the Immune System

Scientists had suspected that genetic factors determine who gets the severe form of the disease and who does not. Evidence for this was seen during outbreaks of this disease, when the severe and deadly form of sepsis was more likely to strike related individuals.

Further evidence was seen in mice, and it was known for years that certain strains of mice are more susceptible to infections with bacteria like N. meningitides--but nobody had ever shown this to be true in humans. Now, the TSRI team found a number of rare mutations in one essential gene in the innate immune system called Toll-like receptor 4 (TLR4), which is important in endotoxin recognition, giving people a higher probability of contracting meningococcal sepsis.

TLR4 is part of the mammalian endotoxin receptor and is an important gene because it detects the early stages of a bacterial infection. It is a powerful pro-inflammatory receptor, responsible for activating the immune system to attack invading gram-negative bacteria like N. meningitidis. During a mammalian innate immune response, TLR4 recognizes endotoxins from the bacteria and activates macrophages, which then ingest and destroy the foreign pathogens.

"The TLRs are the eyes of the innate immune system," says Beutler, who had suspected that these eyes may be myopic for some people and that mutations in the TLR4 gene may underlie the genetic component of severe sepsis.

In order to address this, Beutler looked for extremely rare mutations in the gene by obtaining hundreds of samples of DNA from his collaborator Martin L. Hibberd, then a doctor at Imperial College in London (Hibberd has since taken a position at the Genome Institute of Singapore). He then amplified and sequenced the entire TLR4 gene from each patient, looking for all the rare mutations that are present in the gene--rather than taking the traditional approach of looking at one common mutation within that gene.

After the researchers had analyzed all the genetic information, they found a significant excess of low frequency mutations in the TLR4 genes of the people who had contracted sepsis versus the control group.

Instead of asking how many people have one given mutation, Beutler and his colleagues simply asked how many people have any genetic variation. A few individuals had the same mutations, but by and large they were single, isolated mutations. "However," warns Beutler, "we can only account for a certain fraction of the [genetic] risk."

Nevertheless, this is the first time that a comparison of the collective mutations at a given genetic locus has been made in any infectious disease. Infectious diseases are, after all, primarily caused by an invading organism, and only in recent times has a concerted effort been made to find genetic determinants of susceptibility in the patient. Beutler and his team had to write special software to make the comparison of the thousand different sequences possible and find the individual mutations therein. Significantly, the technique of measuring the genetic variation “load” of the entire gene locus could be applied to other sorts of diseases as well: particularly diseases in which both genes and environment play a role.



The article, "Assay Of Locus-Specific Genetic Load Implicates Rare Tlr4 Mutations in Meningococcal Susceptibility," is authored by Irina Smirnova, Navjiwan Mann, Annemiek Dols, H. H. Derkx, Martin L. Hibberd, Michael Levin, and Bruce Beutler. The article will be available online the week of April 28, 2003 at: http://www.pnas.org/cgi/doi/10.1073/pnas.10311605100, and will be published in an upcoming issue of the journal Proceedings of the National Academy of Sciences. Journalists can request a preprint of the paper from pnasnews@nas.edu.


This work was supported by The National Institutes of Health and also by the Meningitis Research Foundation, a United Kingdom charity.

Jason Bardi | EurekAlert!
Further information:
http://www.scripps.edu/
http://www.pnas.org/cgi/doi/10.1073/pnas.10311605100

More articles from Health and Medicine:

nachricht Using fragment-based approaches to discover new antibiotics
21.06.2018 | SLAS (Society for Laboratory Automation and Screening)

nachricht Scientists learn more about how gene linked to autism affects brain
19.06.2018 | Cincinnati Children's Hospital Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Graphene assembled film shows higher thermal conductivity than graphite film

22.06.2018 | Materials Sciences

Fast rising bedrock below West Antarctica reveals an extremely fluid Earth mantle

22.06.2018 | Earth Sciences

Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View

22.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>