Hemolysin

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Leukocidin/Hemolysin toxin
Staphylococcus aureus alpha toxin from S. aureus (PDB: 7AHL​).
Identifiers
SymbolLeukocidin
PfamPF07968
Pfam clanCL0636
InterProIPR036435
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Hemolysins

pathogens
do not cause significant destruction of red blood cells during infection. However, hemolysins are often capable of lysing red blood cells in vitro.

While most hemolysins are protein compounds, some are lipid biosurfactants.[1]

Properties

Many bacteria produce hemolysins that can be detected in the laboratory. It is now believed that many clinically relevant

fungi also produce hemolysins.[2]
Hemolysins can be identified by their ability to lyse red blood cells in vitro.

Hemolysis by Streptococcus seen on a plate

Not only are the erythrocytes affected by hemolysins, but there are also some effects among other blood cells, such as

macrophages, leading them to autolysis
and death.

Visualization of hemolysis (UK: haemolysis) of red blood cells in agar plates facilitates the categorization of Streptococcus.

Mechanism

One way hemolysin lyses erythrocytes is by forming pores in

phospholipid bilayers.[3][4]
Other hemolysins lyse erythrocytes by hydrolyzing the phospholipids in the bilayer.

Pore formation

Many hemolysins are

cytoplasmic membrane
.

Hemolysin is normally secreted by the bacteria in a water-soluble way. These monomers diffuse to the

heptamer complexes.[5]

Hemolysins can be secreted by many different kinds of bacteria such as Staphylococcus aureus, Escherichia coli or Vibrio parahemolyticus among other pathogens. We can take a look at the bacterium

osmotic swelling
leading to the cell wall rupture (lysis) can cause death of the host cell.

This pore consists of seven alpha-hemolysin subunits, which represent the major cytotoxic agent that is freed by this kind of bacterium. These subunits attach to the target cells in the manner described before, and extend the lipid bilayer, forming the pore structures. These pores in the cellular membrane will eventually end up causing cell death, since it allows the exchange of monovalent ions that would cause the DNA fragmentation.

Enzymatic

Some hemolysins damage the erythrocyte membrane by cleaving the phospholipids in the membrane.

Staphylococcus aureus hemolysins

α-hemolysin

Alpha(α)-hemolysin of Staphylococcus aureus: macromolecular structure of the transmembrane pore.

Secreted by Staphylococcus aureus, this toxin binds with the outer membrane, with subsequent oligomerization of the toxin monomers to form water-filled channels.[6] These are responsible for osmotic phenomena, cell depolarization and loss of vital molecules (v.gr. ATP), leading to cell death.[7]

β-hemolysin

β-hemolysin (hlb; Q2FWP1) is a

phosphoryl-choline due to the release of organic phosphorus from sphingomyelin and ultimately caused cell lysis.[8]

γ-Hemolysin

γ-Hemolysins are pore-forming toxins in the same family as α-Hemolysin. They are unique in that they come in two components, and hence are referred to as bi-component toxins (InterPro: IPR003963). Compared to beta-hemolysin, it has a higher affinity for phosphocholines with short saturated acyl chains, especially if they have a conical form, whereas cylindrical lipids (e.g., sphingomyelin) hinder its activity. The lytic process, most commonly seen in leucocytes, is caused by pore formation induced by an oligomerized octamer that organizes in a ring structure. Once the prepore is formed, a more stable one ensues, named β-barrel. In this final part, the octamer binds with phosphatidylcholine.[9]

Structure

The structure of several hemolysins has been solved by

octameric
.

The heptamer of α-hemolysin from Staphylococcus aureus has a mushroom-like shape and measures up to 100 Å in diameter and 100 Å in height. A membrane-spanning, solvent-accessible channel runs along the sevenfold

hydrophobic interactions, and these contacts provide a molecular stability for the heptamer in SDS solutions even up to 65 °C.[13]

Role during infection

Hemolysins are thought to be responsible for many events in host cells. For example, iron may be a

free radicals, free iron is typically maintained at low concentrations within the body. Red blood cells are rich in iron-containing heme
. Lysis of these cells releases heme into the surroundings, allowing the bacteria to take up the free iron. But hemolysin is related to bacteria not only in this way but also in some others.

As mentioned before, hemolysin is a potential virulence factor produced by

pathologies, many cases of hemolysis do not suppose a health hazard. But the fact that hemolysins (produced by pathogenic microorganisms
during infections) are combined with other virulence factors may threaten a human's life to a greater extent.

The main consequence of hemolysis is

arrhythmias, an enlarged heart or even heart failure, among others.[15]

Depending on the type of hemolysin and the microorganism that produces it, manifestation of symptoms and diseases may differ from one case to the other:

Both aerolysin and alpha-hemolysin are synthesized by extracellular bacteria, which infect specific tissue surfaces.

Hemolysins have proved to be a damaging factor for vital organs, through the activity of

antibodies of anti alpha-hemlysin are thought to give protection.[17]

Further findings show that the main virulence factor of S. aureus, the pore-forming toxin α-hemolysin (Hla), is the secreted factor responsible for the activation of an alternative autophagic pathway. It has been demonstrated that this autophagic response is inhibited by artificially elevating the intracellular levels of cAMP.[18] This process is also mediated by the exchange factors RAPGEF3 and RAP2B.

Another interesting point is that pretreatment of

E. coli attack.[19]

Some hemolysins, such as listeriolysin O, allow bacteria to evade the immune system by escaping from phagosomes. Hemolysins may also mediate bacterial escape from host cells.

Regulation of gene expression

The regulation of gene expression of hemolysins (such as streptolysin S) is a system repressed in the presence of iron.[20] This ensures that hemolysin is produced only when needed. The regulation of the production of hemolysin in S.aureus(expression of hemolysin) is now possible due to in-vitro mutations that are related to serine/threonine kinase and phosphatase.[21]

Treatment

As hemolysins are produced by pathogenic organisms, the main treatment is the intake of antibiotics specific to the pathogen that have caused the infection. Moreover, some hemolysins may be neutralized by the action of anti-hemolysin

antibodies
, preventing a longer and more dangerous effect of hemolysis within the body.

When blood cells are being destroyed too fast, extra

folic acid and iron supplements may be given or, in case of emergencies, a blood transfusion. In rare cases, the spleen must be removed because it filters blood and removes dead or damaged cells from the bloodstream, worsening the lack of erythrocytes.[22]

Applications

Medicine

Thermostable Direct Hemolysin (TDH;

colon carcinoma cells. TDH induces Ca2+ influx from an extracellular environment accompanied by protein kinase C phosphorylation. Activated protein kinase C inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR), the rational target of anti-colorectal cancer therapy.[23]

See also

References

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    )
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  5. PMID 22261056
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  6. ^ Krasil’nikov O.V.; Ternovsky, VI.; Tashmukhamedov, BA. Properties of conductivity channels induced in phospholipid bilayer membanes by alpha-staphylotoxin. //Biofizika (Moscow), — 1981.—V. 26, — N.2, —P. 271—276.
  7. ^ McGillivray DJ, Heinrich F, Valincius G, Ignatjev I, Vanderah DJ, Lösche M, Kasianowicz JJ. "Membrane Association of α-Hemolysin: Proteins Functionally Reconstituted in tBLMs". Carnegie Mellon University.
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  15. ^ "What Is Hemolytic Anemia? - NHLBI, NIH". United States National Institutes of Health. 2011-04-01. Retrieved 2012-11-24.
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  22. PMID 19380475
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  23. PMID 22543197
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External links
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