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Sepsis occurs when the body goes too far in its attempt to fight an infection. Immune cells rush, overreact and wreak havoc on tissues and organs, often leading to organ failure and death.
Researchers at the University of California Medical School in San Diego recently discovered that suppressing the enzyme PHLPP1 improved the results in a mouse model of sepsis. PHLPP1 controls many cellular behaviors by removing phosphates (small chemical labels) from other proteins. And, it now turns out that PHLPP1 also influences inflammation.
The study, published on 13 August 2019 in eLife, introduced the possibility that the inhibition of PHLPP1 may form the basis of new treatments for sepsis in humans.
"Most of the research on inflammation usually involves kinases, enzymes that add phosphate labels to other proteins," said Alexandra Newton, lead author, PhD, professor in the department of pharmacology of the United States. UC San Diego School of Medicine. "It's exciting to have a brand new target for sepsis: the enzymes that kill them."
Newton's team discovered PHLPP1 a few years ago and has since detailed its role in suppressing tumors. Following these results, Newton contacted Chris Glbad, PhD, a fellow inflammation specialist, a colleague of the San Diego School of Medicine.
Together, their teams discovered many immune cell genes influenced by PHLPP1. But the particular influence of PHLPP1 on inflammation could be related to the fact that it removes phosphates from a transcription factor called STAT1, known to control inflammatory genes.
Newton's team took modified mice so that they did not possess the PHLPP1 gene to another colleague of the UC College of Medicine in San Diego, Victor Nizet, MD, an expert in bacterial infections. In separate experiments, the Nizet team administered live E. coli bacteria and lipopolysaccharide (LPS), a cell wall component of the bacterium that drives the immune system in the wild, to mice deficient in PHLPP1 and normal.
The difference surprised Newton: mice without PHLPP1 are much better off. Although all normal mice died of infection-induced sepsis after five days, half of the PHLPP1 deficient mice survived.
Newton's team was already working with other collaborators to screen thousands of chemical compounds to identify those that inhibit PHLPP1. Now that they know that PHLPP1 inhibitors may form the basis of new anti-sepsis drugs, the researchers hope to test these compounds on immune cells in the laboratory and in the mouse model of sepsis.
Currently, sepsis is treated by preventing and treating infection at the source, often with antibiotics, while maintaining organ health with oxygen and intravenous fluids. Nevertheless, according to the Centers for Disease Control and Prevention, at least 1.7 million adults in the United States develop sepsis each year, resulting in the death of nearly 270,000 people. One in three patients who died at the hospital has sepsis.
"Sepsis is the leading cause of death in intensive care units around the world, but unfortunately, there is not a single approved drug treatment for sepsis," Nizet said. "Findings like ours on fundamental signaling pathways that control immune cell behavior during sepsis provide clues to control the dangerous inflammation of sepsis while preserving the crucial bacterial killing properties of white blood cells."
Reference: Ksenya Cohen Katsenelson, et al. (2019) PHLPP1 counter-regulates STAT1 mediated inflammatory signaling. eLife DOI: https://doi.org/10.7554/eLife.48609.001
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