A helminth protein, or

helminthic Parasitic worms, also known as helminths, are large macroparasites; adults can generally be seen with the naked eye. Many are intestinal worms that are soil-transmitted and infect the gastrointestinal tract. Other parasitic worms such as sch ...

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

, is a protein derived from a parasitic

worm Worms are many different distantly related bilateral animals that typically have a long cylindrical tube-like body, no limbs, and no eyes (though not always). Worms vary in size from microscopic to over in length for marine polychaete wor ...

that causes an

immune In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...

reaction. When secreted, these

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

may modify the host's immune response in order to promote longevity of the parasite. Helminth proteins can result in a deregulated response to

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

, and are implicated in reduced reactivity to other

s. Other helminth proteins promote parasite survival in other ways, particularly since parasites must depend on hosts for the supply of essential nutrients. Despite their pathogenic properties, helminth proteins have potential to be co-opted to treat a number of other human diseases.

Immunoregulation

Helminth proteins modulate the immune response of their hosts, but do not suppress it entirely. A number of proteins are able to induce production of IL-10, an anti-inflammatory cytokine. IL-10 is partially responsible for reducing expression of co-stimulatory molecules such as CD86 on

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s. CD86 is one of the proteins which interact with

CD28 CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provid ...

to activate

T helper cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

s; without it, T helper cell response is mitigated.

Schistosome ''Schistosoma'' is a genus of trematodes, commonly known as blood flukes. They are Parasitism, parasitic flatworms responsible for a highly significant group of infections in humans termed ''schistosomiasis'', which is considered by the World H ...

proteins also contain abundant

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

s which and cleave

IgE Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isotype") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε c ...

antibodies. Alpha-1, a protein released by schistosome eggs, can also be a

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

binding protein, preventing the recruitment of other immune cells like

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

s. ''T. canis'' C-type

lectin Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in rec ...

s are additionally able to bind to mammalian

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...

s, suggesting that they may promote evasion of the host's immune system by preventing the migration of host immune cells. A number of helminth species also secrete high levels of

antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...

s to avoid phagocytosis; those antioxidants are needed because phagocytes like macrophages frequently produce reactive oxygen species like oxygen

radicals Radical may refer to: Politics and ideology Politics *Radical politics, the political intent of fundamental societal change *Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe and ...

, superoxide, and

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3%� ...

to attack parasites. Additionally, many

nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-Parasitism, parasitic nematodes also known as eelworms. They are a diverse animal phylum inhab ...

s residing in the gut may secrete

acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...

, which is responsible for the degradation of

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

to terminate neuronal signals. Acetylcholinesterase may prevent parasite clearance from the gut by preventing acetylcholine-mediated signaling from stimulating the production of intestinal

chloride The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...

and

mucus Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It is ...

Lipid Acquisition

Parasites like helminths do not synthesize their own

fatty acid In chemistry, particularly 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, fr ...

s or

sterol Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the go ...

s, and are consequently dependent on their hosts for

essential nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...

s. A number of different classes of lipid-binding proteins have been investigated and characterized. Of these, NPA (nematode polyprotein antigen/allergen) FAR, and Sj-FABPc demonstrate different

binding affinities 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 ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...

for

s and/or

retinoid The retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth. Retinoids have many important functions throughout t ...

s. Ov-FAR-1, which is produced by the riverblindness parasite ''Onchocerca volvulus'' binds

retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xerophtha ...

with great affinity, and this activity may result in the pathology it causes. Ov-FAR-1, however, binds fatty acids with less affinity. On the other hand, Sj-FABPc, found in '' Schistosoma japonicum'', binds fatty acids with high affinity, but does not bind to retinol. All three of these proteins are able to deliver lipids to acceptor

membranes A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...

, but this transfer process in Ov-FAR-1 and ABA-1A1 (a type of NPA) requires an aqueous

diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...

step. Sj-FABPc uses a collision mechanism, and transfer is not affected by changing salt concentrations, suggesting that it may be important to intracellular targeted transport and

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

of fatty acids. Ov-FAR-1 and ABA-1A1 may instead behave similarly to extracellular lipid-binding proteins.

Genomic Prediction

The Helminth Secretome Database (HSD) is a repository for helminth proteins predicted using expressed sequence tags (ESTs). Previously identified ESTs, which correspond to known helminth proteins, are used to predict the location and function of newly discovered helminth proteins based on genomic sequencing. Additionally, the database can also be used to develop protein targets for new drugs to treat helminth infections.

Potential Therapeutics

Given the modulatory properties of helminth proteins, it has been suggested that they may be co-opted to successfully treat other human diseases, particularly those associated with auto-immunity disorders. In particular, immunization with P28GST, a schistosome glutathione ''S''-transferase enzyme in rats has been shown to reduce colitis lesions and expression of pro-inflammatory cytokines by eosinophil responses to inflammation. P28GST is thus a promising potential therapeutic for treating

inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...

s like

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...

and ulcerative colitis. Additionally, injection of proteins secreted by ''

Fasciola hepatica ''Fasciola hepatica'', also known as the common liver fluke or sheep liver fluke, is a parasitic trematode (fluke or flatworm, a type of helminth) of the class Trematoda, phylum Platyhelminthes. It infects the livers of various mammals, inc ...

'' in nonobese diabetic mice prevented the onset of

type I diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

, with 84% of the mice showing normal glucose levels 26 weeks after injection. This phenomenon is attributed to the suppression of

interferon-gamma Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

secretion from autoreactive T cells following the activation of regulatory M2 macrophages. This result supports the possibility of eventually using helminth products to treat type I diabetes in humans as well.

References

{{reflist, 33em Animal proteins Platyhelminth biology