Immunity: Molecular 'criminal' responsible for cell death and inflammation discovered

A study led by wehi has identified a molecular "culprit" that causes damage levels of cell death and inflammation in the body

Cell death is an important part of the body's immune response to infection

The findings, published in the journal Immunity, highlight the potential to create drugs that block caspase-8 and nitric oxide to prevent this new process of inflammatory cell death

• Nitric oxide, and the protein caspase-8 that makes it, have been shown to cause a unique type of cell death that leads to high levels of inflammation in the body

  
  

• The team showed that blocking the activity of caspase-8 and nitric oxide in preclinical models of SARS-CoV-2 reduced inflammation and infection severity

  
  

• The findings suggest that targeting this new cell death pathway may lead to the creation of new treatments for a range of diseases where levels of nitric oxide damage, cell death and inflammation occur, including asthma, inflammatory bowel disease and COVID-19.

  
  

killer's culprit

While nitric oxide is critical to the body's circulatory and nervous systems, recent research has linked overproduction of this molecule to excessive cell death and inflammation

Associate Professor James Vince said the team was surprised to find that nitric oxide was the 'killer' responsible for excessive cell death in the newly discovered inflammatory cell death pathway

"Our study of the combined role of pathogens and host inflammatory molecules in the process of cell death leads directly to nitric oxide," Associate Professor Vince said

"This led us to discover how nitric oxide is a major driver of cell death in this particular pathway

COVID-19 Impact

The team, in collaboration with WEHI infectious disease researchers Prof.

Removal of caspase-8 or nitric oxide in these models most likely prevented cell death and tissue damage, said lead researcher and doctoral student Daniel Simpson, and underscored the potential of using caspase-8 as a drug target, Excessive cell death and subsequent inflammatory response can be prevented

"While this is still preliminary data, we believe that blocking the function of caspase-8, or nitric oxide production, will prevent damaging levels of inflammation," he said

The team used WEHI's CRISPR technology system to dissect new cell death pathways from a genetic perspective and further understand the role of related key genes

Dr Rebecca Feltham said DNA editing techniques were used to create genetic mutations to identify which genes promote nitric oxide production in the cell death pathway
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"Combined with our COVID-19 model, this technology allows us to understand the exact role of caspase-8
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Being able to understand and manipulate key genes in this pathway has potential implications for asthma, inflammatory bowel disease and SARS-CoV-2 Diseases such as viruses lead to exciting new treatment options
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article title

Interferon-g primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway