Flagellin vs Radiation
The Australian ( July 18, 2009 )
New Drug Shields Against
Radiation
by Rabinovich
A
medication that can protect people exposed to normally
lethal doses of radiation from a nuclear or a "dirty" bomb
has been developed, reports say.
In tests involving 650 monkeys exposed to radiation
equivalent to that recorded during the Chernobyl nuclear
reactor disaster in 1986, 70 per cent died while the rest
suffered serious maladies, the newspaper Yediot Achronot said
yesterday.
Of the group given anti-radiation shots, almost all survived
and had no side effects. A test on humans not exposed to
radiation showed none suffered side effects from the
medication.
The medication was developed by Andrei Gudkov, chief
scientific officer at Cleveland BioLabs in the US. Also
involved was Israel's Elena Feinstein.
"We made a breakthrough that may save the lives of
millions," Dr Gudkov was quoted as saying.
The medication has important implications in the treatment
of cancer, the report said, since it permits use of more
powerful radiation.
If the medication is given final approval by the Food and
Drug Administration, which Dr Gudkov said would happen
within two years, it could have a strategic impact,
particularly for nations threatened with nuclear attack.
Among the major fears in the West is not nuclear attack but
"dirty bombs", which kill mostly by radiation.
Dr Gudkov conceived the idea in 2003 of using protein
produced in bacteria found in the intestine to protect cells
from radiation. "The medication works by suppressing the
'suicide mechanism' of cells hit by radiation," the
newspaper said, "while enabling them to recover from the
radiation-induced damages that prompted them to activate the
suicide mechanism in the first place."
The medication is a preventative drug administered by one or
several doses.
Flagellin
Flagellin is a protein that arranges itself in a hollow
cylinder to form the filament in bacterial flagellum. It has
a mass of about 30,000 to 60,000 daltons. Flagellin is the
principal substituent of bacterial flagellum, and is present
in large amounts on nearly all flagellated bacteria.
Structure
The structure of flagellin is responsible for the helical
shape of the flagellar filament, which is important for its
proper function.
The N- and C-termini of flagellin form the inner core of the
flagellin protein, and is responsible for flagellin's
ability to polymerize into a filament. The central portion
of the protein makes up the outer surface of the flagellar
filament. While the termini of the protein is quite similar
between all bacterial flagellins, the central portion is
wildly variable.
Immune response
In mammals
Mammals often have acquired immune responses (T-cell and
antibody responses) to flagellated bacterium occurs
frequently to flagellar antigens. Some bacteria are able to
switch between multiple flagellin genes in order to evade
this response.
The propensity of the immune response to flagellin may be
explained by two facts:
First, flagellin is an extremely abundant protein in
flagellated bacteria.
Secondly, there exists a specific innate immune receptor
that recognizes flagellin, Toll-like receptor 5 (TLR5).
In plants
In addition a 22 amino acid sequence (flg22) of the
conserved N-terminal part of flagellin is known to activate
plant defence mechanisms. Flagellin perception in
Arabidopsis thaliana functions via the receptor-like-kinase,
FLS2 (flagellin-sensitive-2)).
Mitogen-activated-protein-kinases (MAPK) acts as signalling
compounds and more than 900 genes are affected upon flg22
treatment.
Pre-stimulation with a synthetic flg22-peptide led to
enhanced resistance against bacterial invaders.
http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?mode=&term=Flagellin\
MeSH Heading -- Flagellin
Tree Number -- D12.776.097.380
Annotation - a bact protein
Scope Note -- A protein with a molecular weight of
40,000 isolated from bacterial flagella. At appropriate pH
and salt concentration, three flagellin monomers can
spontaneously reaggregate to form structures which appear
identical to intact flagella.
Bacterial flagellin activates basolaterally
expressed TLR5 to induce epithelial proinflammatory gene
expression.
Gewirtz AT, Navas TA,
Lyons S, Godowski PJ, Madara JL.
Epithelial Pathobiology Division, Department of Pathology
and Laboratory Medicine, Emory University, Atlanta, GA
30322, USA ski@gene.com.
Flagellin, the structural component of bacterial flagella,
is secreted by pathogenic and commensal bacteria. Flagellin
activates proinflammatory gene expression in intestinal
epithelia. However, only flagellin that contacts basolateral
epithelial surfaces is proinflammatory; apical flagellin has
no effect. Pathogenic Salmonella, but not commensal
Escherichia coli, translocate flagellin across epithelia,
thus activating epithelial proinflammatory gene expression.
Investigating how epithelia detect flagellin revealed that
cell surface expression of Toll-like receptor 5 (TLR5)
conferred NF-kappaB gene expression in response to
flagellin. The response depended on both extracellular
leucine-rich repeats and intracellular Toll/IL-1R homology
region of TLR5 as well as the adaptor protein MyD88.
Furthermore, immunolocalization and cell surface-selective
biotinylation revealed that TLR5 is expressed exclusively on
the basolateral surface of intestinal epithelia, thus
providing a molecular basis for the polarity of this innate
immune response. Thus, detection of flagellin by basolateral
TLR5 mediates epithelial-driven inflammatory responses to
Salmonella.
WO2005056042
METHODS OF PROTECTING AGAINST
RADIATION USING FLAGELLIN
Abstract --The invention
relates to a method of protecting a mammal against radiation
comprising administering said mammal a composition
containing flagellin.