A WEHI-led study has identified a molecular ‘culprit’ responsible for cell death and inflammation in the body. The findings could lead to improved treatment options for a range of conditions driven by inflammatory cell death, including the SARS-CoV-2 virus.
Cell death is an important part of the body’s immune response to infection. When left unchecked, however, it can cause harmful amounts of inflammation in otherwise healthy organs and tissues. The research team discovered how an overproduction of the molecule nitric oxide, which the caspase-8 protein helps produce, caused dangerous levels of cell death. They showed that shutting down caspase-8 function could prevent unregulated cell death and inflammation.
Posted in Immunity, the results highlight the potential for creating drugs that block caspase-8 and nitric oxide to prevent this novel inflammatory cell death process. Manipulating this cell death pathway could lead to new and improved treatments for people living with inflammatory disease.
The study was led by PhD student Daniel Simpson, Associate Professor James Vince and Dr Rebecca Feltham of WEHI, in collaboration with researchers from Monash University, Australian National University, Institute of Medical Research Hudson and the German University of Cologne.
In one look
- Nitric oxide and the protein that enables its production, caspase-8, have been shown to cause a unique form of cell death that can lead to excessive levels of inflammation in the body.
- The team showed that blocking caspase-8 and nitric oxide activity in a preclinical model of SARS-CoV-2 reduced the severity of inflammation and infection.
- The results suggest that targeting this new cell death pathway could create new therapies for a range of diseases characterized by damaging levels of nitric oxide, cell death and inflammation, including asthma, inflammatory diseases of the gut and COVID-19.
While nitric oxide is essential to the body’s circulatory and nervous systems, recent findings link overproduction of the molecule to excessive levels of cell death and inflammation. Cell death is essential for a healthy immune response, however, too much of it can send the immune system into overdrive and trigger inflammatory disease.
Associate Professor James Vince said the team was surprised to find that nitric oxide was a “culprit killer” responsible for excessive cell death in the recently discovered inflammatory cell death pathway.
“Our research into the combined actions of pathogens and host inflammatory molecules in the process of cell death led us directly to nitric oxide,” said Associate Professor Vince.
“This led us to discover how nitric oxide is the main driver of cell death in this particular pathway. Our study showed that levels of this molecule increased when immune cells detected viral and pathogenic threats. The more there had nitric oxide, the more likely the cells were to die.”
Consequences of COVID-19
Working with WEHI infectious disease researchers Professor Marc Pellegrini, PhD student James Cooney, Dr Marcel Doerflinger and Dr Kathryn Davidson, the team found that blocking the production of nitric oxide and caspase -8, cell death protein, reduced disease severity in a preclinical SARS-CoV-2 infection model.
Lead researcher and doctoral student Daniel Simpson said removing caspase-8 or nitric oxide in these models most likely prevents cells from dying and causing tissue damage, highlighting the potential for caspase’s use. -8 as a drug target that could block excessive cell death and subsequent inflammatory reaction.
“Although this is still preliminary data, we believe that blocking caspase-8 function, or nitric oxide production, would prevent damaging levels of inflammation,” he said. .
The team leveraged WEHI’s CRISPR technology systems to genetically dissect the novel cell death pathway and better understand the role of key genes involved.
Dr Rebecca Feltham said DNA editing technology was used to create mutations in genes to determine which genes facilitate nitric oxide production in this cell death pathway.
“Coupled with our COVID-19 models, this technology has allowed us to understand the exact role of caspase-8. Being able to understand and manipulate key genes in this pathway could lead to exciting new treatment options for diseases where harmful nitric oxide has been suggested. like asthma, inflammatory bowel disease and the SARS-CoV-2 virus,” she said.
The research was supported by the NHMRC, the German Research Foundation, the Leukemia and Lymphoma Society and the Australian Research Council. Wehi Authors: Daniel Simpson, Jiyi Pang, Ashley Weir, Isabella Kong, Maryam Rashidi, James Cooney, Kathryn Davidson, Sebastian Hughes, Liana Mackiewicz, Merle Dayton, Holly Anderton, Marcel Doerflinger, Yexuan Deng, Allan Shuai Huang, Sandra Nicholson, Joanna Groom, Marco Herold, Edwin Hawkins, Andreas Strasser, John Silke, Marc Pellegrini and Rebecca Feltham.