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Pertussis caused by Pertussis toxin

B. Pertussis is a bacterium that is responsible for causing whooping cough. The symptoms and signs develop as a result of action of the Pertussis toxin on the upper respiratory tract (containing ciliated ciliated pseudostratified columnar epithelium). The individual develops several episodes of uncontrollable coughing. The characteristic whoop sound is heard during the cough. It develops especially when the individual is breathing in. The individual also develops fever, diarrhoea and a running nose .

Before understanding the mechanism by which the toxin acts (that is a transduction mechanism), it is important that the physiology of transduction is understood. Receptors are present on the surface of a cell which helps it to communicate with its external world. Specific molecules bind with these receptors present in the external environment and are recognised by the cell. Once these molecules bind to the receptors a cascade of intracellular signals may be produced which brings about several processes and actions in the cell.

A number of antigens or molecules can be recognised by receptors preset on the surface of the cell, following which signals are transmitted within the cell. The lymphocyte cells can bind with and recognise several antigens (belonging to various microorganism and foreign substances). The receptors which are present on the surface of the lymphocytes are made up of complexes containing multiple proteins. Some of the antigens are capable of binding with receptors present on the surface of the lymphocyte and stimulate them to divide further or differentiate into specific effectors cells having a certain function.

Some of the antigens are also capable of brining about death of degeneration of the cell. The receptors present on the two types of lymphocytes may be different from each other and are able to recognise different molecules or antigens. However, in both lymphocytes, the intracellular signal pathway is similar. Ultimately, the nucleus is activated and alterations occur in the genes to enable a reaction from the lymphocyte (including gene expression) . Receptors are present on the surface of the cell, where molecules bind, and the cell is able to identify the molecule that has attached.

The receptor proteins are able to produce a signal once the molecule has attached to the receptor. This signal is transmitted across the plasma membrane, and brings about intracellular events. Signal transduction is a process by which signals are transformed from one form to another. The transformation of the intracellular signal ensures that the message is transmitted in a forward direction, to its destination. The signal may be transmitted to various portions of the cell and may be also get amplified. Finally, the nucleus receives the intracellular signal and the genetic transcription helps to bring about division of the cell .

Most of the studies conducted currently for signal transduction were performed on animals, and only a few are conducted on human subjects . Hence, a lot need to be studied in the field of signal transduction. In some receptors present on the surface of the cell, once antigens are bound with specific molecules, certain ion channels are opened up and an ionic gradient exists that works as an intracellular signal. In certain other cells, when the receptor combines with the molecule, a change in the protein occurs that causes the cytoplasm to get stimulated, resulting in transmission of intracellular signals.

When the receptor combines with the specific molecule, a signal is transmitted that enables the receptors to cluster on the surface of the cell. This clustering results in the receptor producing a very strong signal. The exact manner in which the receptors

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clustering occur is still not understood. However, if the cell contacts another cell that has several copies of the MHC protein complex, they begin to recognise it and cluster around . The receptors present on the cell, usually bring about intracellular signals by stimulating the enzyme protein tyrosine kinase (they add phosphate group to tyrosine residues).

The receptors on the cytoplasmic front contain tyrosine kinase that is usually inactive. However, when clustering occurs, they begin to stimulate each other through transphosphorlyation, which further activate the biochemical signalling molecules present in the cytoplasm. On the antigen front of the receptor, no tyrosine kinase is available and hence the cytoplasmic front combines with the tyrosine kinase present in the cytoplasm. During clustering, the enzymes are closer to each other, which help to activate the intracellular signalling mechanism.

The biochemical activity of the cell is regulated by phosphorylation of the enzymes and proteins by the tyrosine kinase. Phosphorylation makes certain enzymes active, and once they are dephosphorylated (by the enzyme protein phosphatase), they become inactive. Once an enzyme is phosphorylated, new binding sites are created for the target proteins . Phospholipase C-gamma enzyme is present at the tyrosine receptor or the plasma membrane and can attach itself to phosphotryrosine. This enzyme amplifies and forwards the signal.

Once tyrosine kinase gets phosphrylated, the phopholipid is broken down into 2 components, namely DAG and IP3. Many DAG and IP3 molecules are produced from single molecules of PLC-gamma, and in this way the signal gets amplified. The IP3 combines with the receptors present on the endoplasmic reticulum, causing the release of calcium ions, and thus raising the level of calcium intracellularly. The signal is maintained even when the Calcium ions are exhausted, as calcium channels present on the cell membrane are opened and the extra-cellular calcium flows in.

The Calcium ion binding protein Calmodulin is also activated that controls the activity of other enzymes present in the cell. The signal is transmitted to the nucleus. DAG on the other hand activates the enzyme Protein kinase C. They may act in several mechanisms to finally ensure that the signal has reached the nucleus . Calmodulin also controls the activity of the enzyme adenylate cyclase produced by the human cell GTP-proteins help to transmit the signal from the tyrosine kinase receptors to the nucleus. Ras is the most common type of GTP-proteins.

It may be activated once the molecule comes in contact with the receptor. Ras can be bound to GTP or GDP. The GDP form of Ras is inactive compared to the GTP. This inter-conversion is brought about by the enzyme Ras-GTPase. Usually, the GTP-proteins are present in an inactive form and are activated once the specific molecule comes in contact with the receptor. GDP can also be converted to GTP by GEF’s. Activation of GTP-proteins leads to activation of several protein kinases (known as ‘MAP-kinase’). MAP-kinase can bring about phophrylation and activation of nucleus transcription .

B. Pertussis sticks to the cell with the help of “filamentous hemagglutinin” (FHA). The Pertussis Toxin also helps to bind the bacterial cell to the host cell. During the colonization of the bacteria, the toxin plays a very important role in invasion . The substance Filamentous hemagglutinin (FHA) produced by B. Pertussis combines with the receptor integrin present on the plasma membrane. This in turn stimulates increased binding of another portion of FHA with another receptor present on the plasma membrane known as ‘complement receptor-3’ (CR-3).

In this way as the binding of the B. Pertussis antigen is increased with the receptors present on the plasma membrane, the signal produced is strong . The Pertussis Toxin mainly helps the bacterial cell to attach itself to the epithelium of the trachea. The Pertussis toxin is made up of 5 subunits (obtained through the process of gel electrophoresis), namely S-1, S-2, S-3, S-4 and S-5. In fact, the S-4 component is two in number . The subunit S-4 is present in a larger ratio compared to the others.

The Pertussis toxin has two components namely, A-promoter (S-1) which brings about the toxin enzymatic activity, and B-oligomer (S-2, S-3, S-4 and S-5), which helps the toxin to bind to the receptor present on the plasma membrane. The Pertussis toxin produces several physiological effects including rise in the lymphocyte count, activating the islet cells to release greater amounts of insulin and exaggerating the effects of histamine. The physiological effects of Pertussis toxin mainly brings about it effect on the G-i component of the adenylate cyclase.

The toxin works by ADP-ribosylation of G-i protein provided by the S-1 component of the toxin . Compared to normal stimuli, activation with the Pertussis toxin results in greater accumulation of the cAMP within the cells. Agents that obstruct production of cAMP are inactivated by the Pertussis toxin. When the cell is affected with Pertussis toxin and toxin acts on G-i protein, the responses to various chemotactic agents are reduced, suggesting that G-i plays a very important role in the development of immunity.

Transducin is Guanine-protein present in the rods and the cones that activates cyclic AMP-selective phosphodiesterase. ADP-ribosylation of tranducin is also stimulated by Pertussis toxin . By altering the manner in which G-proteins are bound, the bacterial toxin can obstruct the signal transduction process. The toxin brings about ADP-ribosylation of certain alpha subunits of the G-protein component of adenylate cyclase namely G-i, G-o, G-t, G-gust, and G-s is not converted to G-olf. Once G-i is ribosylated, the enzyme adenylate cyclase is reduced increasing the level of cAMP .

Once the levels of cAMP are raised, the function of the phagocytic cells is reduced (such as chemotaxis, engulfment, bactericidal action, etc) . The S-1 component of the Pertussis toxin is united with the B-oligomer portion in a non-covalent manner. The B-oligomer portion helps the toxin to attach to the receptor present on the plasma membrane. Without the B-oligomer portion, the S-1 component of the Pertussis toxin is unable to pass through the cell . The S-2 and the S-3 components of the Pertussis Toxin mainly help in adhesion of the cell to the host cells.

Ciliated epithelial cells contain a glycolipid that helps the S-2 component to bind, whereas the phagocyctic cells contain glycoprotein that helps to bind the S-3 component . Certain opioid receptors are present on the surface of the cell that is linked with the G-protein receptor family. Once the opioid receptors have been activated by the Pertussis toxin, the G-proteins that are sensitive to the Pertussis toxin (namely G-i and/or G-o) are stimulated. The ADP-ribose portion of the NAD is transferred to the G-i. G-i gets inactivated and does not obstruct adenylate cyclase.

The intracellular concentration of cAMP increases because the transformation of ATP to AMP cannot be controlled . This results in generation of an intracellular signal which activates the gene transcription in the nucleus and brings about cell division. Once the opioid receptor has been activated, the enzyme Adenylate cyclase is decreased and the Cyclic AMP levels present in the cell are increased. Calcium channels are repressed and inward flow of potassium ions are stimulated by the opioid receptors. When the opioid receptors were stimulated, neuronal excitability reduced.

Opioid receptors activation can also bring about activation of the MAP-kinase. Once this occurs, arachidonate may be released and genes c-fos and jun-B are expressed . BvgA and BvgS proteins help the B. Pertussis to express adhesions, virulence factors and toxins. BvgA appear similar to the regulator component, whereas BvgS appears similar to the regulator and sensory component. This system helps to bring about phosphorylation cascade following sensory inputs. As transmission and receiving can occur in this system, a signal pathway system does exist.

The cytoplasmic front of the BvgS autophosphorylates with ATP (r-phosphate portion). BvgA is phosphorylated following transfer of BvgS of the phosphate group to the Asp. Gene expression may occur in relation to phosphrylation of BvgA . The human IL-1 stimulates release of kappa Ig-L by the pre-B Cell lines, IL-2R by the Natural Killer cell Lines and PGE2 by the rheumatoid synvovial cells. However, all these IL-stimulated factors are reduced by the Pertussis toxin, which may be associated the cAMP production.

As IL-1 stimulates GTPase activity, Pertussis Toxin brought about a reduction in GTPase activity. Pertussis toxin also stimulated ADP-ribosylation of the enzyme adenylate cyclase in the membrane of cells that are usually activated in cells sensitive to IL-1 . Once the cell is affected with the Pertussis toxin, agents that would otherwise obstruct the collection of cAMP are no longer effective. The Pertussis toxin brings about certain cell transduction mechanism that further enables the cell to be invaded by the microorganism .

Many of the bacterial toxins such as Cholera Toxin, E. coli labile toxin and the Pertussis toxin act in the same manner and produce the same effect (that is a rise in the cAMP levels of the cell). However, the symptoms and signs of each of these disorders are different. This is mainly because the target tissues and cells of each of these toxins are different. The Pertussis toxin mainly acts on the epithelium of the respiratory tract causing several symptoms such as whoop, cough, breathing problems and cyanosis .

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