Plasma Gelsolin
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Plasma gelsolin (pGSN) is an 83 kDa abundant
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
constituent of normal plasma and an important component of the
innate immune system The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...
. The identification of pGSN in ''
Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (an insect of the Order (biology), order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly" ...
'' and ''
C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...
'' points to an ancient origin early in evolution. Its extraordinary structural conservation reflects its critical regulatory role in multiple essential functions. Its roles include the breakdown of filamentous actin released from dead cells, activation of
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s, and localization of the
inflammatory response Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
. Substantial decreases in plasma levels are observed in acute and chronic infection and injury in both
animal models A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Mod ...
and in humans. Supplementation therapies with recombinant human pGSN have been shown effective in more than 20 animal models. pGSN has a cytoplasmic isoform (cGSN) known to be an actin-binding protein controlling
cytoskeletal The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all Cell (biology), cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane ...
dynamics. cGSN is expressed from the same gene, and is identical to pGSN except for its lack of a 24
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
extension.


History

The cellular isoform of Gelsolin was discovered in 1979 in the lab of
Thomas P. Stossel Thomas P. Stossel (September 10, 1941 – September 29, 2019) was an American hematologist, inventor, medical researcher, and writer, who discovered gelsolin and invented the BioAegis technology estate. He was also a professor emeritus of medicine ...
. Its name comes from observed calcium-dependent reversible ''gel-sol'' transitions of macrophage cytoplasmic extract. Around the same time a similarly sized plasma protein was discovered and shown to depolymerize actin; it was named Brevin, due to its ability to shorten actin filaments. In 1986 it was demonstrated that Brevin was identical to cellular Gelsolin except for a 24 AA N-terminal extension, and was renamed Plasma Gelsolin.


Structure

Plasma Gelsolin is a 755 AA, 83 kDa plasma protein made up of six "gelsolin domains," each composed of a 5-6 strand
β-sheet The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...
between one long and one short
α-helix An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...
. It exhibits a weak homology between domains S1 and S4, S2 and S5, and S3 and S6, and is identical to the cytoplasmic form of the protein except for the addition of a 24 AA N-terminal extension. Additionally a 27 AA N-terminal
signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16–30 amino acids long) present at the ...
is cleaved prior to pGSN's secretion from the cell. Both forms of the protein are encoded by highly conserved genes on
chromosome 9 Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of DN ...
in humans, but are under the control of different promoters. There is a single
disulfide In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inorg ...
bond formed on the second domain of the plasma protein, there are no documented natural
post-translational modifications In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...
, and the pI ≈ 6.


Isoforms and mutations

Aside from the cellular form, the only other known isoform is Gelsolin-3, an identical non-secreted protein containing an 11 AA, rather than 24 AA, N-terminal extension. It has been found in brain, testes, and lung
oligodendrocytes Oligodendrocytes (), also known as oligodendroglia, are a type of neuroglia whose main function is to provide the myelin sheath to neuronal axons in the central nervous system (CNS). Myelination gives metabolic support to, and insulates the axon ...
, and is reportedly involved in
myelin Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...
remodeling during spiralization around the
axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
. Plasma Gelsolin is highly conserved, and its only known mutations are single point mutations. One of several such mutations leads to Finnish Familial Amyloidosis, a disorder in which pGSN becomes more conformationally flexible and susceptible to enzymatic cleavage resulting in accumulation of peptide fragments into
amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...
fibrils. D187N/Y is the most common mutation with additional reports of G167R, N184K, P432R, A551P, and Ala7fs in the medical literature. In addition to this several mutations as well as down-regulation of the protein are associated with breast cancer.


Ca2+

At moderate pH in the absence of Ca2+ pGSN is compact and globular. Low pH or the presence of >nM Ca2+ is associated with an elongated structure with greater backbone flexibility. This flexibility exposes the actin binding sites. Since physiological levels of Ca2+ are ~2 mM, pGSN is natively elongated and able to bind to leaked actin from cellular damage.


Functions


Binding

Plasma Gelsolin is a sticky protein known to bind to a number of peptides and proteins:
Actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
(see: Relationships with actin), Apo-H,
Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor pr ...
,
α-Synuclein Alpha-synuclein (aSyn) is a protein that in humans is encoded by the ''SNCA'' gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters. Alpha-synuclein is abundant in the bra ...
,
Integrin Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...
,
Tcp-1 HSP60, also known as chaperonins (Cpn), is a family of heat shock proteins originally sorted by their 60kDa molecular mass. They prevent misfolding of proteins during stressful situations such as high heat, by assisting protein folding. HSP60 be ...
,
Fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as col ...
, Syntaxin-4,
Tropomyosin Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in many animal and fungal cells. In animals, it is an important component of the muscular system which works in conjunction with troponin to regulate muscle contraction. It ...
,
fatty acids In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
and
phospholipids Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typi ...
(see: Binding and inactivation of diverse inflammatory mediators): LPA, LPS (endotoxin), LTA, PAF, S1P, polyphosphoinositides including PIP2; and nucleic acids: Ap3A, ATP, ADP. PIP2, a phospholipid component of cell membranes, competes with ATP and actin for pGSN binding, and will dissociate F-Actin-capped pGSN.


Relationships with actin


Actin toxicity and removal

Actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
is the most abundant cellular protein, and its release into extracellular fluid and circulation following cellular injury from disease or injury leads to increased blood viscosity, hindered microcirculation, and activation of platelets. Hemodialysis patients with low levels of pGSN and high levels of actin in blood had markedly higher mortality. Actin is a major component of
biofilms A biofilm is a syntrophic community of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular polymer ...
that accumulate at local sites of injury and infection, impeding access of host immune components and therapeutics such as antibiotics. Biofilms are particularly pathogenic in the setting of foreign bodies like indwelling catheters and tissue implants. Actin exchanges between monomeric (G) and filamentous (F) forms according to the concentrations of it, ATP, and cations. pGSN along with
Vitamin D-binding protein Vitamin D-binding protein (DBP), also/originally known as gc-globulin (group-specific component), is a protein that in humans is encoded by the ''GC'' gene. DBP is genetically the oldest member of the albuminoid family and appeared early in the ev ...
(DBP) bind and clear monomeric actin. DBP binds with greater affinity to G-actin, leaving pGSN available to sever F-actin. Furthermore, DBP is capable of removing one actin from a 2:1 actin-pGSN complex, restoring its ability to sever F-actin. F-actin, severed and capped by pGSN, is removed by sinusoidal endothelial cells of the liver. pGSN removes 60% of actin trapped in fibrin clots ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' leading to an increased rate of clot lysis.


Severing, capping, nucleation, and polymerization

Although pGSN is capable of initiating the polymerization of actin through
nucleation In thermodynamics, nucleation is the first step in the formation of either a new Phase (matter), thermodynamic phase or Crystal structure, structure via self-assembly or self-organization within a substance or mixture. Nucleation is typically def ...
, its primary relationship with it in blood is depolymerization through filament severing. Actin severing occurs rapidly in the presence of pGSN and Ca2+. pGSN wraps around filaments, non-enzymatically cleaving them. It remains attached, "capping" the barbed/plus end of the severed filament and inducing a torsional twist that is cooperative through its length. Capping has a reported
binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usuall ...
<250 pM in the presence of Ca2+ that is substantially weakened in its absence. Capping also blocks further polymerization at the fast growing, barbed end. While no evidence exists for nucleating/polymerizing of G-actin by pGSN ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
'', the ability of it to do so ''in vitro'' is well documented. Actin polymerization is initiated by the production of an actin trimer nucleus. Formation of nuclei is energetically disfavored, but dimers and/or trimers can be catalyzed/stabilized by a number of cellular proteins. In excess of a 2:1 actin:gelsolin
stoichiometry Stoichiometry () is the relationships between the masses of reactants and Product (chemistry), products before, during, and following chemical reactions. Stoichiometry is based on the law of conservation of mass; the total mass of reactants must ...
and in the presence of Ca2+, gelsolin will bind three actin monomers. A monomer adds to the trimer creating a
tetramer A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula ...
that undergoes an internal conversion to an active tetramer witnessed by a concentration-independent lag phase. Subsequent fibrilization proceeds by monomer addition. Gelsolin remains attached to the fast-growing (barbed/plus) end of actin, producing short, slow-growing fibrils. These actions are similar to those of cytoplasmic form of pGSN, cGSN, which contributes to structural changes of cells through both nucleating/polymerizing and severing/capping.


Amyloid prevention and clearance

pGSN may play an important role in the prevention and management of
amyloidosis Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weigh ...
in several diseases. It is found in complex with
Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor pr ...
in plasma and reported to both inhibit amyloid formation and defibrillize preformed fibrils ''in vitro''. Mice with an
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
model given pGSN showed a 5-fold decrease in progression of
Cerebral Amyloid Angiopathy Cerebral amyloid angiopathy (CAA) is a form of angiopathy in which amyloid beta peptide deposits in the walls of small to medium blood vessels of the central nervous system and meninges. The term ''congophilic'' is sometimes used because the pres ...
. pGSN has also been found in
Lewy Bodies Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside neurons affected by Parkinson's disease (PD), the Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)) ...
, amyloid containing protein aggregates associated with
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
and
Dementia with Lewy bodies Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior change (individual), behavior, cognition, movement, and dysautonomia, regulation of automatic bodily functions. Unlike some other dementias, mem ...
.


Role in inflammation


Macrophage stimulation


MARCO receptor

Macrophage receptor
MARCO Marco may refer to: People Given name * Marco (actor) (born 1977), South Korean model and actor Surname * Georg Marco (1863–1923), Romanian chess player of German origin * Jindřich Marco (1921–2000), Czechoslovak photographer and numismat ...
is responsible for pathogen recognition and phagocytosis. Macrophages incubated with actin at concentrations consistent with lung injury showed decreased uptake of bacteria. Uptake was restored when actin was administered in the presence of pGSN.


NOS3

NOS3 Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the ''NOS3'' gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms tha ...
is an
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that is protective against systemic inflammation and myocardial dysfunction. pGSN activates phosphorylation of Ser1177 in NOS3 and Ser473 in
Akt Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tra ...
. NOS3 is known to be activated by phosphorylation of Akt. Mouse macrophage uptake and killing of bacteria ''in vitro'' was enhanced by pGSN, and no significant enhancement was found for NOS3-/- macrophages. ''In vivo'', mice showed 15-fold improvement in bacterial clearance when given pGSN, and no significant enhancement was found for NOS3-/- mice.


Inflammatory mediators

pGSN has been shown to bind to the fatty acid inflammatory mediators LPA, LPS (endotoxin), LTA, PAF, S1P, and polyphosphoinositides including PIP2. Mediators of inflammation, the body's innate healing mechanism, accumulate at the site of the injury to begin the processes of defense and repair, and the depletion of local pGSN allows them to do their work. See Binding and inactivation of diverse inflammatory mediators


Therapeutic potential

The broad therapeutic potential of pGSN supplementation resides in the fact that the molecule embodies a multifunctional system contributing importantly to innate immunity rather than a pharmacologic intervention with selective and specific activities. Plasma gelsolin's primary function is to keep inflammation local and enhance the function of the innate immune system. It functions through a
pleiotropic Pleiotropy () is a condition in which a single gene or genetic variant influences multiple phenotypic traits. A gene that has such multiple effects is referred to as a ''pleiotropic gene''. Mutations in pleiotropic genes can impact several trait ...
mechanism of action; severing toxic filamentous actin (
F-actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
), binding inflammatory mediators, and enhancing pathogen clearance. These mechanisms are quite distinct from other
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...
agents that function as
antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.inhibitors of specific enzymes, and work to
ablate Ablation ( – removal) is the removal or destruction of something from an object by vaporization, chipping, erosive processes, or by other means. Examples of ablative materials are described below, including spacecraft material for ascent and ...
inflammation. Most systemic anti-inflammatory agents also suppress the immune system and often require caution in administration because they increase the risk of infection. Plasma gelsolin is unique in that it has also been demonstrated to enhance the antimicrobial action of macrophages, which engulf and digest cellular debris and pathogens, boosting immunity against both gram positive and gram negative bacterial infections.


Mechanisms of action

Plasma gelsolin plays a central role in the body's innate immune system and is responsible for localizing inflammation—a mechanism so central to species survival that it has been highly conserved by evolution. Experimental and epidemiology data suggest that pGSN performs the role of a buffer or shield that modulates the inflammatory response to injury or infection. The system accomplishes this goal in three key ways described below:


Debridement

Plasma gelsolin binds and severs filamentous actin exposed from cells damaged by injury, including both infectious and sterile injury. Actin has been reported to activate platelets, interfere with
fibrinolysis Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other c ...
, damage
endothelial The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...
cells, and to function as a danger signal ( DAMP). Administration of large quantities of filamentous actin to rats resulted in lethal pulmonary hemorrhage and thrombosis. Another key “toxicity” of exposed actin is the fact that it is a major component of
biofilms A biofilm is a syntrophic community of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular polymer ...
that accumulate at local sites of injury and infection, and that it impedes the access of host immune components and therapeutics such as antibiotics. Biofilms are particularly pathogenic in the setting of foreign bodies like indwelling catheters and tissue implants. As a result of actin exposure at the local site of injury, the local level of plasma gelsolin around the site of the injury initially becomes depleted as it “debrides” the local involved site. Mediators of inflammation, the body's innate healing mechanism, accumulate at the site of the injury to begin the processes of defense and repair, and the depletion of local plasma gelsolin allows them to do their work. While local pGSN levels are depressed, the presence of this abundant protein in the circulation ensures that the inflammatory process stays local, and that stores of plasma gelsolin are available to address further injury so that the overall immune response remains intact.


Augmentation of macrophage antimicrobial activity

pGSN has antimicrobial activity ''in vitro'' and ''in vivo''. Administration of pGSN subcutaneously or by inhalation to mice challenged with lethal inocula of ''S. pneumoniae'' or even more lethal combinations of influenza virus and bacteria markedly diminished the number of viable bacteria in the animals’ airways and significantly reduced mortality. The number of inflammation-inducing neutrophils was also considerably reduced, presumably as a result of enhanced bacterial clearance. This is true for contemporaneous or delayed administration of recombinant pGSN. A basis of pGSN's antimicrobial action is that it enhances the ability of cultivated lung macrophages to ingest gram positive and gram negative bacteria. This has been demonstrated ''in vitro''. Improved phagocytosis is the product of pGSN debriding actin bound to macrophage scavenger receptors preventing their function. pGSN also increases the ability of macrophages to kill ingested microorganisms by inducing macrophage
nitric oxide synthase Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristal ...
activity.


Binding and inactivation of diverse inflammatory mediators

pGSN binds to a number of inflammatory mediators and signaling agents. Binding to LPA occurs at the same site on the molecule that ligates actin and interacts with polyphosphoinositides. Subsequent studies showed that gelsolin alters the effector function of LPA's receptor binding. Binding to inflammatory mediators, and in some cases inhibition of their effector function, has been shown for platelet-activating factor, lipopolysaccharide endotoxin, sphingosine-1-phosphate, and lipoteichoic acid and small molecule
purinergic Purinergic receptors, also known as purinoceptors, are a family of plasma membrane molecules that are found in almost all mammalian tissues. Within the field of purinergic signalling, these receptors have been implicated in learning and memory, ...
agonists including ATP and ADP. The binding of pGSN to
Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor pr ...
Alzheimer peptide has also been well documented.


Anti-microbial resistance

Antimicrobial resistance Antimicrobial resistance (AMR or AR) occurs when microbes evolve mechanisms that protect them from antimicrobials, which are drugs used to treat infections. This resistance affects all classes of microbes, including bacteria (antibiotic resista ...
is a global threat that leads to an estimated 700,000 deaths annually with projections of 10M deaths per year and lost economic potential of $100T by 2050. The United States has released a national action plan to combat antibiotic resistant bacteria. Recombinant pGSN (rhu-pGSN) supplementation alone shows improved survival and decreased bacteria counts in several mouse models. The
bactericidal A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics. However, material surfaces can also have bactericidal properties based solely on their p ...
activity of the
antimicrobial peptide Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for ...
LL-37 Cathelicidin antimicrobial peptide (CAMP) is an antimicrobial peptide encoded in the human by the ''CAMP'' gene. The active form is LL-37. In humans, ''CAMP'' encodes the peptide precursor CAP-18 (18 kDa), which is processed by proteinase 3-media ...
was shown to be inhibited by F-actin. It formed bundles with F-actin ''in vitro'' that were dissolved by pGSN, restoring bactericidal activity. Bacteria growth was reduced when pGSN was added
cystic fibrosis Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...
sputum Sputum is mucus that is coughed up from the lower airways (the trachea and bronchi). In medicine, sputum samples are usually used for a naked-eye examination, microbiological investigation of respiratory infections, and Cytopathology, cytological ...
, which is known to contain F-actin. When mice were given a
penicillin Penicillins (P, PCN or PEN) are a group of beta-lactam antibiotic, β-lactam antibiotics originally obtained from ''Penicillium'' Mold (fungus), moulds, principally ''Penicillium chrysogenum, P. chrysogenum'' and ''Penicillium rubens, P. ru ...
-resistant strain of
pneumococcal pneumonia Pneumococcal pneumonia is a type of bacterial pneumonia that is caused by Streptococcus pneumoniae (pneumococcus). It is the most common bacterial pneumonia found in adults, the most common type of community-acquired pneumonia, and one of the co ...
, penicillin had no effect on mortality or
morbidity A disease is a particular abnormal condition that adversely affects the structure or function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical conditions that are asso ...
. rhu-pGSN improved both mortality and morbidity on its own, and the combination of rhu-pGSN and penicillin gave further improvement of both suggesting possible
synergism In Christian theology, synergism refers to the cooperative effort between God and humanity in the process of Salvation in Christianity, salvation. Before Augustine of Hippo (354–430), synergism was almost universally endorsed. Later, it came to ...
.


Levels of the Protein

Plasma gelsolin is produced and secreted by virtually every cell type with muscle contributing the largest amount. At normal levels of >200 mg/L, it is a highly abundant protein in the circulation. Decreased levels are often associated with ill health and disease. A growing list of insults showing loss of pGSN includes
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
,
sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...
, SIRS,
traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity ranging from mild traumatic brain injury (mTBI/concussion) to severe traumati ...
,
autoimmune diseases An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that ...
,
chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
,
HIV-1 The subtypes of HIV include two main subtypes, known as HIV type 1 (HIV-1) and HIV type 2 (HIV-2). These subtypes have distinct genetic differences and are associated with different epidemiological patterns and clinical characteristics. HIV-1 e ...
disease,
tick-borne encephalitis Tick-borne encephalitis (TBE) is a virus, viral infectious disease involving the central nervous system. The disease most often manifests as meningitis, encephalitis or meningoencephalitis. Myelitis and spinal paralysis also occur. In about one ...
and Lyme,
malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...
,
hepatitis Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...
, burns,
multiple organ dysfunction syndrome Multiple organ dysfunction syndrome (MODS) is altered organ function in an acutely ill patient requiring immediate medical intervention. There are different stages of organ dysfunction for certain different organs, both in acute and in chronic ...
,
trauma Trauma most often refers to: *Psychological trauma, in psychology and psychiatric medicine, refers to severe mental and emotional injury caused by distressing events *Traumatic injury, sudden physical injury caused by an external force, which doe ...
associated with
injury Injury is physiological damage to the living tissue of any organism, whether in humans, in other animals, or in plants. Injuries can be caused in many ways, including mechanically with penetration by sharp objects such as teeth or with ...
or
surgery Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery s ...
,
bone marrow transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce a ...
, and
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
. Severely depleted levels (<150 mg/L) strongly correlate with the onset of systemic inflammatory dysregulation and predict increased morbidity and mortality across a broad spectrum of clinical presentations in the critical care setting. The magnitude of decline in pGSN correlates with the likelihood of mortality in seriously ill patients. Mediators of inflammation, the body's innate healing mechanism, accumulate at the site of the injury to begin the processes of defense and repair, and the depletion of local plasma gelsolin allows them to do their work. As a result of actin exposure at the local site of injury, the local level of plasma gelsolin around the site of the injury initially becomes depleted as it “debrides” the local involved site (see:
Debridement Debridement is the medical removal of dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue. Removal may be surgical, mechanical, chemical, autolytic (self-digestion), or by maggot therapy. In ...
). While local pGSN levels are depressed, the presence of this abundant protein in the circulation ensures that the inflammatory process stays local, and that stores of plasma gelsolin are available to address further injury so that the overall immune response remains intact (see: Binding and inactivation of diverse inflammatory mediators). Measured levels are higher in serum than plasma due to pGSN's affinity for
fibrin Fibrin (also called Factor Ia) is a fibrous protein, fibrous, non-globular protein involved in the Coagulation, clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerization, polymerize. ...
.


Animal studies

Human plasma gelsolin has been produced in recombinant form in ''
E. coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escherichia'' that is commonly foun ...
'' (rhu-pGSN), and its efficacy as a therapeutic has been studied ''in vivo'' in a number of animal models of inflammatory disease. In models of injury that cause actin release and inflammatory organ damage, pGSN levels consistently drop. In models where gelsolin levels are replenished, adverse outcomes can be prevented. To date, rhu-pGSN has been studied in many independent laboratories providing evidence of efficacy in >20 animal models. Following are descriptions of selected animal studies. All stated results are relative to those of
placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...
treatments.


Human Studies

In 201
BioAegis Therapeutics
conducted a Phase Ib/IIa safety study administering recombinant human pGSN to sick patients with community acquired
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
; no safety issues were found. A 2020 Phase IIb placebo-controlled efficacy study has been approved for acute severe pneumonia due to
COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic. The symptoms of COVID‑19 can vary but often include fever ...
. The primary outcome was the proportion of patients surviving on Day 14 without mechanical ventilation, vasopressors, or dialysis. Evaluation of efficacy of rhu-pGSN was confounded by high survival rates of both treatment and placebo cohorts resulting from improvements made to the standard of care for COVID pneumonia.


See also

Cytoplasmic gelsolin
Actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
Vitamin D-binding protein Vitamin D-binding protein (DBP), also/originally known as gc-globulin (group-specific component), is a protein that in humans is encoded by the ''GC'' gene. DBP is genetically the oldest member of the albuminoid family and appeared early in the ev ...


References

{{Reflist Proteins