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ANU research find protein responsible for body's self-destruction during sepsis

A joint Australian-American research team's work has paved the way for the prevention of an immune system reaction responsible for what one scientist described as the "body killing itself by trying to get rid of bacteria".

The scientists from the Australian National University, the Garvan Institute of Medical Research and American biotechnology company Genentech​ have identified the gene that causes inflammations leading to sepsis, a bodily response to infections that can worsen a patient's condition and cause vital organs to shut down.

Sepsis develops as a complication from pre-existing infections, causing a self-destructive immune response that John Curtin School for Medical Research's Professor Simon Foote said counterproductively overwhelmed the body.

He said in the worst cases, the body's bloodstream could leak into organs or cause septic shock, resulting in a one-in-two chance of survival.

"An infection alone doesn't give you the outcomes that the body's response to the infection causes," Professor Foote said.

"The immune response to bugs overwhelms the body itself."

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An estimated million people die from sepsis every year in the United States alone.

The ANU, Garvan and Genentech researchers discovered the protein Gasdermin-D was critical to the development of sepsis, before working to find the gene responsible for producing it.

The isolation of that gene took slightly more than a year, a timeframe far shorter than the researchers expected, with a large-scale forward genetics discovery platform.

Ordinarily a dormant part of a cell, Gasdermin-D becomes active when an enzyme known as capase-11 cuts the chemical cap off the protein, causing a chemical reaction leading to a cell's self-destruction.

Capase-11 itself is triggered by the invasion of cells by molecules known as lipopolysaccharides, or LPS, which come from the surface of some bacteria.

Researchers knew LPS was directly related to the self-destructive immune response causing sepsis, but did not know how the implosion happened.

Their discovery, built on decades of research from ANU Emeritus Professor Philip Board, could lead to drugs that could stop the immune system from fatal self-destruction, though it won't eliminate sepsis entirely.

"This offers the potential for therapy, because all you need is a drug that inhibits the function of this particular enzyme," Professor Foote said.

"It still means we have to treat the infection, but the overwhelming response from the host no longer occurs." 

The next challenge is to create a drug that works in the human body, but which also acts quickly enough to combat the rapid development of sepsis.

Further research will also be undertaken to determine not just how the chemical reaction in the cell happens, but why.

Genentech senior scientist Nobuhiko Kayagaki said the benefits of the research would stretch beyond the treatment of sepsis

"The identification of Gasdermin-D can give us a better understanding not only of lethal sepsis, but also of multiple other inflammatory diseases," he said.

A research paper on the findings was published in Nature in September.