Trypanosoma cruzi
Overview
 
Trypanosoma cruzi is a species of parasitic euglenoid trypanosome
Trypanosoma
Trypanosoma is a genus of kinetoplastids , a monophyletic group of unicellular parasitic flagellate protozoa. The name is derived from the Greek trypano and soma because of their corkscrew-like motion. All trypanosomes are heteroxenous and are transmitted via a vector...

s. This species causes the trypanosomiasis
Trypanosomiasis
Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. Approximately 500,000 men, women and children in 36 countries of sub-Saharan Africa suffer from human African trypanosomiasis which is caused by...

 diseases in humans and animals in America. Transmission occurs when the reduviid bug
Reduviidae
Reduviidae is a large, cosmopolitan family of predatory insects in the suborder Heteroptera...

 deposits feces on the skin surface and subsequently bites; the human host then scratches the bite area, which facilitates penetration of the infected feces.

Human American trypanosomiasis, or Chagas disease
Chagas disease
Chagas disease is a tropical parasitic disease caused by the flagellate protozoan Trypanosoma cruzi. T. cruzi is commonly transmitted to humans and other mammals by an insect vector, the blood-sucking insects of the subfamily Triatominae most commonly species belonging to the Triatoma, Rhodnius,...

, has two forms, a trypomastigote found in human blood and an amastigote
Amastigote
An amastigote is a cell that does not have a visible external flagella or cilia. The term is used mainly to describe a certain phase in the life-cycle of trypanosome protozoans. It is also called the leishmanial stage, since in Leishmania it is the form the parasite takes in the vertebrate host,...

 found in tissues.
Encyclopedia
Trypanosoma cruzi is a species of parasitic euglenoid trypanosome
Trypanosoma
Trypanosoma is a genus of kinetoplastids , a monophyletic group of unicellular parasitic flagellate protozoa. The name is derived from the Greek trypano and soma because of their corkscrew-like motion. All trypanosomes are heteroxenous and are transmitted via a vector...

s. This species causes the trypanosomiasis
Trypanosomiasis
Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. Approximately 500,000 men, women and children in 36 countries of sub-Saharan Africa suffer from human African trypanosomiasis which is caused by...

 diseases in humans and animals in America. Transmission occurs when the reduviid bug
Reduviidae
Reduviidae is a large, cosmopolitan family of predatory insects in the suborder Heteroptera...

 deposits feces on the skin surface and subsequently bites; the human host then scratches the bite area, which facilitates penetration of the infected feces.

Human American trypanosomiasis, or Chagas disease
Chagas disease
Chagas disease is a tropical parasitic disease caused by the flagellate protozoan Trypanosoma cruzi. T. cruzi is commonly transmitted to humans and other mammals by an insect vector, the blood-sucking insects of the subfamily Triatominae most commonly species belonging to the Triatoma, Rhodnius,...

, has two forms, a trypomastigote found in human blood and an amastigote
Amastigote
An amastigote is a cell that does not have a visible external flagella or cilia. The term is used mainly to describe a certain phase in the life-cycle of trypanosome protozoans. It is also called the leishmanial stage, since in Leishmania it is the form the parasite takes in the vertebrate host,...

 found in tissues. The acute form usually goes unnoticed and may present as a localized swelling at the site of entry. The chronic form may develop 10 to 20 years after infection. This form affects internal organs (e.g., the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

, the esophagus
Esophagus
The esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...

, the colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...

, and the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...

). Affected people may die from heart failure.

Acute cases are treated with nifurtimox
Nifurtimox
Nifurtimox is a 5-nitrofuran and is used to treat diseases caused by trypanosomes including Chagas disease and sleeping sickness. It is given by mouth and not by injection.-Indications:...

 and benznidazole
Benznidazole
Benznidazole is an antiparasitic medication used in the treatment of Chagas disease. Its mechanism of action is thought to be inhibition of protein and ribonucleic acid synthesis...

, but there is currently no effective therapy for chronic cases.

Life cycle

Trypanosoma cruzi life cycle starts in an animal reservoir. These reservoirs are usually mammals, wild or domestic, and include humans. A reduviid bug serves as the vector. While taking a blood meal, it ingests T. cruzi. In the reduviid bug, they go into the epimastigote stage. This makes it possible to reproduce. After reproducing through mitosis, the epimastigotes move onto the rectal cell wall. There, they become infectious. Infectious T. cruzi are called trypomastigotes. Then, while the reduviid bug is taking a blood meal from a human, it defecates. The trypomastigotes are in the feces. Trypomastigotes are capable of swimming into the host's cells using flagella, a characteristic swimming tail dominant in the Euglenoid class of protists.

The trypomastigotes enter the human host through the bite wound or by crossing mucous membranes. The host cells contain macromolecules such as laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...

, thrombospondin
Thrombospondin
Thrombospondins are secreted proteins with antiangiogenic abilities. TSP was discovered by Nancy L. Baenziger.-Types:The thrombospondins are a family of multifunctional proteins...

, heparan sulphate, and fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...

 that cover the surface of the host cells. These macromolecules are essential in the adhesion between parasite and host and the invasion process by the parasite of the host. The trypomastigotes must cross a network of proteins that line the exterior of the host cells in order to make contact and invade the host cells. The molecules and proteins on the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

 of the cell also bind to the surface of the parasite and initiate host invasion. When they enter a human cell, they become amastigotes. This is another reproductive stage. After reproducing through mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

 until a large amount of amastigotes are in a cell, pseudocyst
Pseudocyst
Pseudocysts are like cysts, but lack epithelial or endothelial cells. Initial management consists of general supportive care. Symptoms and complications caused by pseudocysts require surgery. CT scans are used for initial imaging of cysts, and endoscopic ultrasounds are used in differentiating...

s are formed in infected cells. The amastigotes then turn back into trypomastigotes, and the cell bursts. The trypomastigotes swim along to either infect other cells or get sucked up by other reduviid bugs.

Myocardial biochemical response

Subcellular findings in murine studies with induced T. cruzi infection revealved that the chronic state is associated with the persistent elevation of phosphorylated (activated) extracellular-signal-regulated kinase (ERK
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...

), AP-1
AP-1
AP1 or AP-1 can refer to:* AP-1 * Autopista AP-1, a Spanish motorway* Caproni AP.1, a 1934 Italian attack aircraft monoplane* USS Henderson...

, and NF-κB. Also, the mitotic regulator for the G1 progression, cyclin D1
Cyclin D1
G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...

, was found activated. It is indicated that, although there was no increase in any isoform of ERK, there was an increased concentration of phosphorylated ERK in T. cruzi–infected mice. It was found that within 7 days the concentration of AP-1 was significantly higher in T. cruzi–infected mice when compared to the control. Elevated levels of NF-κB have also been found in myocardial tissue, with the highest concentrations being found in the vasculature. It was indicated through Western blot
Western blot
The western blot is a widely used analytical technique used to detect specific proteins in the given sample of tissue homogenate or extract. It uses gel electrophoresis to separate native proteins by 3-D structure or denatured proteins by the length of the polypeptide...

 that cyclin D1 was upregulated from day 1 to day 60 post-infection. It was also indicated through immunohistochemistry that the areas that produced the most cyclin D1 were the vasculature and interstitial regions of the heart.

Conduction abnormalities

Also associated with T. cruzi are conduction abnormalities. At the base of these conduction abnormalities is a depopulation of parasympathetic neuronal endings on the heart. Without proper parasympathetic innervations, one could expect to find not only chronotropic
Chronotropic
Chronotropic effects are those that change the heart rate.Chronotropic drugs may change the heart rate by affecting the nerves controlling the heart, or by changing the rhythm produced by the sinoatrial node...

 but also ionotropic abnormalities. It is true that all inflammatory and non-inflammatory heart disease may display forms of parasympathetic denervation; this denervation presents in a descriptive fashion in Chagas’ disease. It has also been indicated that the loss of parasympathetic innervations can lead to sudden death. This sudden death is due to a severe cardiac failure that occurs during the acute stage of infection.

Another conduction abnormality presented with chronic Chagas’ disease is a change in ventricular repolarization. Ventricular repolarization is represented on an electrocardiogram as the T-wave. This change in repolarization inhibits the heart from relaxing and entering diastole
Diastole
Diastole is the period of time when the heart fills with blood after systole . Ventricular diastole is the period during which the ventricles are relaxing, while atrial diastole is the period during which the atria are relaxing...

 properly. Changes in the ventricular repolarization in Chagas’ disease are likely due to myocardial ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...

. This ischemia can also lead to fibrillation
Fibrillation
Fibrillation is the rapid, irregular, and unsynchronized contraction of muscle fibers. An important occurrence is with regards to the heart.-Cardiology:There are two major classes of cardiac fibrillation: atrial fibrillation and ventricular fibrillation....

. This sign is usually observed in chronic Chagas’ disease and is considered a minor electromyocardiopathy.

Another class of electrocardiomyopathies associated with Chagas’ disease are the bundle branch blocks. These include incomplete left bundle branch block, complete left bundle branch block
Bundle branch block
A bundle branch block refers to a defect of the heart's electrical conduction system.-Anatomy and physiology:The heart's electrical activity begins in the sinoatrial node , which is situated on the upper right atrium. The impulse travels next through the left and right atria and summates at the...

 and complete right bundle branch block. These defects occur because of a lack of conduction in the bundle branches, which connect the AV node to the purkinje fibers
Purkinje fibers
For the nervous cells, see Purkinje cellPurkinje fibers are located in the inner ventricular walls of the heart, just beneath the endocardium...

, which mediates a concerted contraction of the ventricles. A bundle branch block is usually associated with a change in the Electrocardiogram
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...

 vector. The ECG vector usually runs straight to the apex of the heart, in a bundle branch block the vector will run to the opposite from the block. Chagasic bundle branch block is presented in chronic Chagas’ disease and is considered a moderate electrocardiomyopathy.

Severe conduction abnormalities associated with Chagas’ disease occurs when a bundle branch block spreads past the bundle of His
Bundle of His
The bundle of His, known as the AV bundle or atrioventricular bundle, is a collection of heart muscle cells specialized for electrical conduction that transmits the electrical impulses from the AV node to the point of the apex of the fascicular branches...

 and creates an atrioventricular block
Atrioventricular block
An atrioventricular block involves the impairment of the conduction between the atria and ventricles of the heart.The causes of pathological AV block are varied and include ischaemia, infarction, fibrosis or drugs. Certain AV blocks can also be found as normal variants, such as in athletes or...

. At this point, the patient will present with impaired conduction velocity and mild bradycardia, or elicit Wenckebach phenomenon depending to the degree of AV block. Also presented with severe Chagas’ cardiomyopathy but lying outside the scope of this subsection would be dyspnea
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...

 and syncope
Syncope (medicine)
Syncope , the medical term for fainting, is precisely defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.Many forms of syncope are...

.

Epicardial lesions

Also associated with Chagas’ disease are epicardial lesions. These lesions include Milk spots, Chagasic rosary, and villous plaque. It has been proposed that these three categories of lesions, although occurring in different areas of the heart and having different histological appearances, are all epicardial reactions to chronic inflammatory responses. These lesions could be the direct cause of conduction problems, thrombosis problems, or even the root of the ventricular remodeling.
Upon examination milk spots are characterized as white areas on ventricular epicardium, with precise borders, and often appear on the right ventricle. Microscopic examination of the anatomy of milk spots shows that they are composed of parallel arrangements of densely compacted collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

 fibers with no vasculature. The location of these fibers may lead to interference with the conduction of current through the heart. It has been proposed that milk spots are actually scars, due to the lack of inflammatory cells and vascular proliferation. Milk spots are not purely indicative of heart conditions related to Chagas’ disease, but are also associated with many chronic heart diseases.

Chagasic rosary refers to small round granules deposited along the coronary vessels. These small round granules are arranged like a string of beads, hence the term rosary
Rosary
The rosary or "garland of roses" is a traditional Catholic devotion. The term denotes the prayer beads used to count the series of prayers that make up the rosary...

. The chagasic rosary structures are composed of the same collagen fibers that milk spots are formed from, the difference between the two being their size and location. The location of chagasic rosary may play a role in the thromboembolism associated with Chagas’ disease. Chagasic rosary is unique to Chagas’ disease; however, it should not be considered a pathognomonic
Pathognomonic
Pathognomonic is a term, often used in medicine, that means characteristic for a particular disease. A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doubt...

 lesion of the chagasic etiology.

Villous plaque is characterized by exophytic epicardial
Epicardial
Epicardial is a term used by some cardiac surgeons meaning "on the outside of the cardiac muscle". Epicardial fat or Epicardial adipose tissue is one of the most important parts of pericardium.See also epicardium....

 thickening, meaning that the growth is occurring at the border of the epicardium and not the center of mass. Unlike milk spots and chagasic rosary, villous plaque has inflammatory cells and vasculature present. Since villous plaque still contains inflammatory cells it is reasonable to suspect that these lesions are more recently formed than milk spots or chagasic rosary.

Cardiac manifestations

Researchers of Chagas’ disease have demonstrated several processes that occur with all cardiomyopathies. The first event is an inflammatory response. Following the inflammation, cellular damage will occur. Finally, in the body’s attempt to recover from the cellular damage, fibrosis will set into the cardiac tissue.

Chagas’ disease can affect myocardial function by causing heart failure syndrome. Depending on which side of the heart is affected by chagasic cardiomypopathies, there will be different clinical manifestations throughout the body. Associated with right side damage will be edema, ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...

, hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...

, and pathologic jugular turgor. The previously mentioned, symptoms are due to inadequate removal of venous blood. Associated with left side damage will be pulmonary congestion and low cardiac output. Also observed in heart failure syndrome is apical aneurysm, sometimes with a diameter between 2–5 cm, weakening the endocardial-pericardial junction.

Arrhythmic syndrome is also a cardiomyopathy clinically associated with Chagas’ disease. The alterations of the contactile rhythms spur from atrioventricular and intraventricular conduction defects, dysfunction of the sinus node, primary and secondary ventricular repolarization disturbance, fibrosis and inflammation, autonomic dysfunction, and endothelial dysfunction.

There is some evidence that chronic Chagas disease also can cause autonomic disfunction, including impaired regulation of heart rate in response to various physiological stresses such as orthostatic testing or the Valsalva maneuver
Valsalva maneuver
The Valsalva maneuver or Valsalva manoeuvre is performed by moderately forceful attempted exhalation against a closed airway, usually done by closing one's mouth and pinching one's nose shut...

.

Another cardiomyopathy found in nearly all cases of chronic Chagas’ disease is Thromoembolic syndrome. Thromboembolism describes thrombosis, the formation of a clot, and its main complication –embolism, the carrying of a clot to a distal section of the vessel and causing blockage. This occurrence contributes to the death of a patient by four means: arrhythmias, stasis secondary to cardiac dilation, mural endocarditis, and cardiac fibrosis. These thrombi also affect other organs such as the brain, spleen and kidney.

External links

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