Molecular 'culprit' caught driving cell death and inflammation

Date:
February 17, 2022
Source:
Walter and Eliza Hall Institute
Summary:
A new study has identified a molecular 'culprit' responsible for
causing damaging levels of 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.



FULL STORY ==========================================================================
A WEHI-led study has identified a molecular 'culprit' responsible
for causing damaging levels of 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 uncontrolled, however, it can cause harmful amounts of inflammation
in otherwise healthy organs and tissue. The research team uncovered
how an overproduction of the molecule nitric oxide, which the protein
caspase-8 helps to produce, caused dangerous levels of cell death. They
showed that arresting the function of caspase-8 could prevent unregulated
cell death and inflammation.

Published in Immunity,the findings highlight the potential to create 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 from WEHI, in collaboration with
researchers from Monash University, Australian National University,
the Hudson Institute of Medical Research and Germany's Cologne University.

At a glance
* Nitric oxide and the protein that enables its production,
caspase-8, have
been shown to cause a unique form of cell death that can drive
excessive levels of inflammation in the body.

* The team showed that blocking the activity of caspase-8 and
nitric oxide
in a preclinical SARS-CoV-2 model reduced the severity of
inflammation and infection.

* The findings suggest targeting this novel cell death pathway
could create
new therapeutics for a range of diseases where damaging levels of
nitric oxide, cell death and inflammation occur including asthma,
inflammatory bowel disease and COVID-19.

Killer culprit While nitric oxide is critical to the body's circulatory
and nervous systems, the recent findings link an overproduction of the
molecule with excessive levels of cell death and inflammation. Cell death
is critical 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 uncover
that nitric oxide was a 'killer culprit' responsible for driving excessive
cell death in the newly discovered inflammatory cell death pathway.

"Our research into the combined actions of pathogen and host inflammatory molecules in the cell death process led us directly to nitric oxide,"
Associate Professor Vince said.

"This led us to discover how nitric oxide is the major driving force
of cell death in this particular pathway. Our study showed levels of
this molecule ramped up when immune cells sensed viral and pathogenic
threats. The more nitric oxide that was made, the more likely it was
that cells would die." COVID-19 implications Collaborating 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 the cell death
protein caspase-8 reduced the severity of disease in a preclinical
SARS-CoV-2 infection model.



==========================================================================
Lead researcher and PhD student Daniel Simpson said removing caspase-8
or nitric oxide in these models most likely stops cells from dying and
causing tissue damage, highlighting the potential to use caspase-8 as
a drug target that could block excessive cell death and the subsequent inflammatory response.

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

The team leveraged WEHI's CRISPR technology systems to genetically
dissect the new cell death pathway and further understand the role of
the key genes involved.

Dr Rebecca Feltham said that DNA editing technology was used to create mutations in genes to determine which genes facilitated nitric oxide
production in this cell death pathway.

"Coupled with our COVID-19 models, this technology 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 damaging nitric oxide has been suggested
to occur such as asthma, inflammatory bowel disease and the SARS-CoV-2
virus," she said.

The research was supported by 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.

========================================================================== Story Source: Materials provided by Walter_and_Eliza_Hall_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Daniel S. Simpson, Jiyi Pang, Ashley Weir, Isabella Y. Kong, Melanie
Fritsch, Maryam Rashidi, James P. Cooney, Kathryn C. Davidson,
Mary Speir, Tirta M. Djajawi, Sebastian Hughes, Liana Mackiewicz,
Merle Dayton, Holly Anderton, Marcel Doerflinger, Yexuan Deng, Allan
Shuai Huang, Stephanie A. Conos, Hazel Tye, Seong H. Chow, Arfatur
Rahman, Raymond S. Norton, Thomas Naderer, Sandra E. Nicholson,
Gaetan Burgio, Si Ming Man, Joanna R. Groom, Marco J. Herold,
Edwin D. Hawkins, Kate E.

Lawlor, Andreas Strasser, John Silke, Marc Pellegrini, Hamid
Kashkar, Rebecca Feltham, James E. Vince. Interferon-g primes
macrophages for pathogen ligand-induced killing via a caspase-8
and mitochondrial cell death pathway. Immunity, 2022; DOI:
10.1016/j.immuni.2022.01.003 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220217141243.htm

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