Protein that keeps immune system from freaking out could form basis for
new therapeutics

Date:
October 14, 2020
Source:
University of California - San Diego
Summary:
Treatment with a peptide that mimics the naturally occurring protein
GIV prevents immune overreaction and supports a mechanism critical
for survival in mouse models of sepsis and colitis, according to
a new study.



FULL STORY ==========================================================================
The immune response to infections is a delicate balance. We need just
enough action to clear away the offending bacteria or viruses, but not
so much that our own bodies suffer collateral damage.


========================================================================== Macrophages are immune cells at the front line, detecting pathogens
and kicking off an inflammatory response when needed. Understanding how macrophages determine when to go all-out and when to keep calm is key to finding new ways to strike the right balance -- particularly in cases
where inflammation goes too far, such as in sepsis, colitis and other autoimmune disorders.

In a study published October 14, 2020 in the Proceedings of the National Academy of Sciences, researchers at University of California San Diego
School of Medicine discovered that a molecule called Girdin, or GIV,
acts as a brake on macrophages.

When the team deleted the GIV gene from mouse macrophages, the immune
cells rapidly overacted to even small amounts of live bacteria or a
bacterial toxin.

Mice with colitis and sepsis fared worse when lacking the GIV gene in
their macrophages.

The researchers also created peptides that mimic GIV, allowing them to
shut down mouse macrophages on command. When treated with the GIV-mimic peptide, the mice's inflammatory response was tempered.

"When a patient dies of sepsis, he or she does not die due to the invading bacteria themselves, but from an overreaction of their immune system to
the bacteria," said senior author Pradipta Ghosh, MD, professor at UC
San Diego School of Medicine and Moores Cancer Center. "It's similar to
what we're seeing now with dangerous 'cytokine storms' that can result
from infection with the novel coronavirus SARS-CoV-2. Macrophages, and
the cytokines they produce, are the body's own immune-stimulating agents
and when produced in excessive amounts, they do more harm than good."
Digging deeper into the mechanism at play, Ghosh and team discovered
that the GIV protein normally cozies up to a molecule called Toll-like
receptor 4 (TLR4). TLR4 is stuck right through the cell membrane, with
bits poking inside and outside the cell. Outside of the cell, TLR4 is
like an antenna, searching for signs of invading pathogens. Inside the
cell, GIV is nestled between the receptor's two "feet." When in place,
GIV keeps the feet apart, and nothing happens. When GIV is removed,
the TLR4 feet touch and kick off a cascade of immune-stimulating signals.

Ghosh's GIV-mimicking peptides can take the place of the protein when
it's missing, keeping the feet apart and calming macrophages down.

"We were surprised at just how fluid the immune system is when it
encounters a pathogen," said Ghosh, who is also director of the Institute
for Network Medicine and executive director of the HUMANOID Center of
Research Excellence at UC San Diego School of Medicine. "Macrophages don't
need to waste time and energy producing more or less GIV protein, they can rapidly dial their response up or down simply by moving it around, and it appears that such regulation happens at the level of gene transcription."
Ghosh and team plan to investigate the factors that determine how the
GIV brake remains in place when macrophages are resting or is removed
to mount a response to a credible threat. To enable these studies,
the Institute for Network Medicine at UC San Diego School of Medicine
recently received a new $5 million grant from the National Institute
of Allergy and Infectious Diseases, part of the National Institutes of
Health. Ghosh shares this award with her colleagues Debashis Sahoo, PhD, assistant professor at UC San Diego School of Medicine and Jacobs School
of Engineering, and Soumita Das, PhD, associate professor of pathology
at UC San Diego School of Medicine.

Co-authors of the study include: Lee Swanson, Gajanan D. Katkar, Julian
Tam, Rama F. Pranadinata, Yogitha Chareddy, Jane Coates, Mahitha Shree Anandachar, Vanessa Castillo, Joshua Olson, Victor Nizet, Irina Kufareva, Soumita Das, all at UC San Diego.


========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Heather
Buschman, PhD. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Lee Swanson, Gajanan D. Katkar, Julian Tam, Rama F. Pranadinata,
Yogitha
Chareddy, Jane Coates, Mahitha Shree Anandachar, Vanessa Castillo,
Joshua Olson, Victor Nizet, Irina Kufareva, Soumita Das, and
Pradipta Ghosh.

TLR4 signaling and macrophage inflammatory responses are dampened
by GIV/ Girdin. PNAS, 2020 DOI: 10.1073/pnas.2011667117 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201014171320.htm

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