Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Single enzyme helps drive inflammation in mice, provides target for new sepsis drugs

14.08.2019

Sepsis occurs when the body goes overboard in its attempt to fight off an infection. Immune cells rush in, overreact and wreak havoc on tissues and organs, often resulting in organ failure and death.

Researchers at University of California San Diego School of Medicine recently found that removing the enzyme PHLPP1 improved outcomes in a mouse model of sepsis.


HeLa cells expressing PHLPP (left), the segment with the nuclear localization signal (middle), and that same segment mutated (right).

Credit: UC San Diego School of Medicine

PHLPP1 controls many cell behaviors by removing phosphates (small chemical tags) from other proteins. And, it now turns out, PHLPP1 also influences inflammation.

The study, published August 13, 2019 in eLife, introduces the possibility that inhibiting PHLPP1 could form the basis for new sepsis treatments in humans.

"Most research on inflammation has typically focused on kinases, enzymes that add phosphate tags to other proteins," said senior author Alexandra Newton, PhD, professor in the Department of Pharmacology at UC San Diego School of Medicine. "It's exciting to have a completely new target for sepsis -- the enzymes that remove them."

Newton's team discovered PHLPP1 a few years ago and have since detailed its role in suppressing tumors. Following up on these findings, Newton reached out to UC San Diego School of Medicine colleague Chris Glass, PhD, an expert on inflammation.

Together, their teams uncovered many immune cell genes that are influenced by PHLPP1. But PHLPP1's particular influence on inflammation could be linked to the fact that it removes phosphates from a transcription factor called STAT1, which is known for controlling inflammatory genes.

Newton's team took mice modified to lack the PHLPP1 gene to another UC San Diego School of Medicine colleague, Victor Nizet, MD, an expert on bacterial infections. In separate experiments, Nizet's team administered live E. coli bacteria and lipopolysaccharide (LPS), a component of the bacterium's cell wall that drives immune systems wild, to both PHLPP1-deficient and normal mice.

The difference surprised Newton: Mice without PHLPP1 fared much better. While all normal mice died of the infection-induced sepsis after five days, half of the PHLPP1-deficient mice survived.

Newton's team had already been working with additional collaborators to screen thousands of chemical compounds to identify those few that inhibit PHLPP1. Now that they know PHLPP1 inhibitors might form the basis for new anti-sepsis drugs, the researchers hope to test these compounds on immune cells in the lab and in the mouse model of sepsis.

Currently, sepsis is addressed by preventing and treating the source infection, often with antibiotics, while maintaining organ health with oxygen and intravenous fluids. Nonetheless, according to the Centers for Disease Control and Prevention, at least 1.7 million adults in the U.S. develop sepsis each year, and nearly 270,000 die as a result. One in three patients who die in a hospital have sepsis.

"Sepsis is the leading cause of death in intensive care units throughout the world, but unfortunately there is not a single approved drug treatment for sepsis," Nizet said. "Discoveries like ours of fundamental signaling pathways that control immune cell behavior during sepsis offer clues for controlling the dangerous inflammation of sepsis while preserving the critical bacterial killing properties of white blood cells."

###

Co-authors include: Ksenya Cohen-Katsenelson, Joshua D. Stender, Agnieszka T. Kawashima, Gema Lordén, Satoshi Uchiyama, all at UC San Diego.

Disclosure: Victor Nizet is a co-founder and scientific advisor for Staurus Pharma, LLC and has equity interest.

Media Contact

Heather Buschman, Ph.D.
hbuschman@ucsd.edu
858-249-0456

 @UCSanDiego

http://www.ucsd.edu 

Heather Buschman, Ph.D. | EurekAlert!
Further information:
http://dx.doi.org/10.7554/eLife.48609

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A cavity leads to a strong interaction between light and matter

Researchers have succeeded in creating an efficient quantum-mechanical light-matter interface using a microscopic cavity. Within this cavity, a single photon is emitted and absorbed up to 10 times by an artificial atom. This opens up new prospects for quantum technology, report physicists at the University of Basel and Ruhr-University Bochum in the journal Nature.

Quantum physics describes photons as light particles. Achieving an interaction between a single photon and a single atom is a huge challenge due to the tiny...

Im Focus: Solving the mystery of quantum light in thin layers

A very special kind of light is emitted by tungsten diselenide layers. The reason for this has been unclear. Now an explanation has been found at TU Wien (Vienna)

It is an exotic phenomenon that nobody was able to explain for years: when energy is supplied to a thin layer of the material tungsten diselenide, it begins to...

Im Focus: An ultrafast glimpse of the photochemistry of the atmosphere

Researchers at Ludwig-Maximilians-Universitaet (LMU) in Munich have explored the initial consequences of the interaction of light with molecules on the surface of nanoscopic aerosols.

The nanocosmos is constantly in motion. All natural processes are ultimately determined by the interplay between radiation and matter. Light strikes particles...

Im Focus: Shaping nanoparticles for improved quantum information technology

Particles that are mere nanometers in size are at the forefront of scientific research today. They come in many different shapes: rods, spheres, cubes, vesicles, S-shaped worms and even donut-like rings. What makes them worthy of scientific study is that, being so tiny, they exhibit quantum mechanical properties not possible with larger objects.

Researchers at the Center for Nanoscale Materials (CNM), a U.S. Department of Energy (DOE) Office of Science User Facility located at DOE's Argonne National...

Im Focus: Novel Material for Shipbuilding

A new research project at the TH Mittelhessen focusses on the development of a novel light weight design concept for leisure boats and yachts. Professor Stephan Marzi from the THM Institute of Mechanics and Materials collaborates with Krake Catamarane, which is a shipyard located in Apolda, Thuringia.

The project is set up in an international cooperation with Professor Anders Biel from Karlstad University in Sweden and the Swedish company Lamera from...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

International Symposium on Functional Materials for Electrolysis, Fuel Cells and Metal-Air Batteries

02.10.2019 | Event News

NEXUS 2020: Relationships Between Architecture and Mathematics

02.10.2019 | Event News

Optical Technologies: International Symposium „Future Optics“ in Hannover

19.09.2019 | Event News

 
Latest News

Kirigami inspires new method for wearable sensors

22.10.2019 | Materials Sciences

3D printing, bioinks create implantable blood vessels

22.10.2019 | Medical Engineering

Ionic channels in carbon electrodes for efficient electrochemical energy storage

22.10.2019 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>