For years it has been known that the protozoan parasite Trypanosoma cruzi is responsible for Chagas disease, infecting more than 18 million people worldwide, with another 120 million people at risk of acquiring this parasite in endemic regions (1). T. cruzi infection in humans occurs when reduviid bug excreta breaks into the skin, and amastigotes enter the body (2). Once inside, the amastigotes differentiate into bloodform trypomastigotes, which specifically target muscle cells, including the heart. The most unusual outcome of this disease is chronic Chagas disease Cardiomyopathy, CCC, which can manifest itself up to 30 years after the initial infection with T. cruzi (1). Patients with this disease show symptoms of myocarditis, which is a weakening of the heart muscles, ventricular enlargements, and cardiac ischemia, a lack of sufficient blood flow to the heart. However, mysteriously, in autopsies of hearts displaying CCC there is no indication of the presence of the parasite (2). Chagas disease cardiomyopathy is distinct from regular congestive heart failure, and the absence of this parasite in the heart leads to the hypothesis that T. cruzi’s effects on the heart are in an indirect manner.
The main reason that the mechanism of pathogeneis of Chagas disease is so difficult to understand is due to the extreme variations in the outcome of infections (1). Acute infections manifest themselves in the form of lesions at the site of infection, and studies have shown that initially after contact, antibodies against myosin, actin and laminin have been detected in host species (2). This means that in some cases T. cruzi begins its degenerative effects on muscles immediately after infecting the host. However, the majority of infected people can be asymptomatic for the remainder of their lives, and only one third of those infected will eventually display Chagas disease cardiomyopathy (1). This makes early detection and treatment of CCC extremely difficult, and in the past hypothesis about the pathogenesis of Trypanosoma cruzi had been dependent solely on autopsies of infected cadaver hearts. Recently, animal models have been used to discover many possible explanations for the secondary affects of T. cruzi on the heart.
The main reason that the mechanism of pathogeneis of Chagas disease is so difficult to understand is due to the extreme variations in the outcome of infections (1). Acute infections manifest themselves in the form of lesions at the site of infection, and studies have shown that initially after contact, antibodies against myosin, actin and laminin have been detected in host species (2). This means that in some cases T. cruzi begins its degenerative effects on muscles immediately after infecting the host. However, the majority of infected people can be asymptomatic for the remainder of their lives, and only one third of those infected will eventually display Chagas disease cardiomyopathy (1). This makes early detection and treatment of CCC extremely difficult, and in the past hypothesis about the pathogenesis of Trypanosoma cruzi had been dependent solely on autopsies of infected cadaver hearts. Recently, animal models have been used to discover many possible explanations for the secondary affects of T. cruzi on the heart.
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| Figure 1. (2) Images of an uninfected and infected heart. Myocyte swelling and necrosis are observed in the muscle tissue of the infected heart. |
Years of extensive research on this topic have yet to reach a definitive conclusion as to the cause of CCC. There are currently six different explanations for T. cruzi related cardiomyopathy, and it is thought that a combination of these, not a single one, are responsible for CCC. The presence of a specific T. cruzi secretion has not yet been demonstrated, however, it has been put forth as an explanation (1,2). This secretion is toxic to host tissues and can continue causing damage even after the parasites are no longer present in the body. Parasite-induced myocytolysis is a mechanism suggested for cardiomyopathy, in which the host cells lyse after the amastigotes differentiate into the trypomastigotes (2). This will initially cause irreparable damage to the heart tissue which may not manifest itself until many years after the infection. Parasite induced microvascualr changes could also be an explanation, depriving the heart of proper oxygen perfusion and leading to chronic inflammation. The majority of explanations for CCC focus on autoimmunity and the ways in which this can come about, including the presence of T. cruzi antigens which can act as a site for specific T cell mediated delayed- type hypersensitivity, leading to damage of host tissues (1). Polyclonal B cell activation is thought to occur after T. cruzi infections, leading to immunosuppresion in the host. Bystander activation, in which T cells specific for one antigen are activated as a result of an immune response against a different antigen, is also thought to play a role in bringing about auto immune responses in Chagas disease infected patients (2).
Researchers have yet to come to a consensus about the most likely cause of autoimmunity leading to Chagas disease cardiomyopathy, however, recently the explanation receiving the most attention is that of molecular mimicry (1). Molecular mimicry occurs when specific sequences between foreign intrusive peptides and self peptides are similar enough to result in a cross- activation of autoreactive T or B cells (4). Occasionally, a single T cell receptor can be activated by foreign residues, which results in autoimmunity. It is thought that the body’s immune response to a T. cruzi protein will crossreact with a self protein sharing a similar target. This causes an immune response to be launched against the host and tissue damage occurs if this response is strong enough (1). There are two combinations hypothesized for molecular mimicry, one is the reaction of the peptides of T cruzi B13 protein with the human cardiac myosin, and the other is the peptides of T cruzi cruzipain and skeletal myosin (1). These cross reactive T. cruzi proteins are thought to cause autoimmunity, which then results in the progressive degeneration of all muscles, especially the heart. It has also been shown that human cardiac myosin from Chagas disease patients can specifically recognize a T. cruzi antigen (1). It was also found that cardiac myosin antibodies were present in 100% of sera from CCC patients, but not in healthy patients. Myosin specific autoimmunity caused in part by molecular mimicry is apparently one of the most common causes of cardiac myopathy.
It is currently impossible to determine if any of these parasite induced effects are the sole reason for cardiomyopathy, and in reality is it mostly likely a combination of autoimmunity and anti-parasite immunity and other factors that result in eventual cardiac death (1,2). The only cure for CCC is a heart transplant, and therefore discovering the pathogenesis of T. cruzi is of extreme importance. Until the exact mechanism of parasite induced autoimmunity is discovered, appropriate treatments will be impossible to find, and the T. cruzi killer will still be at large, claiming more than 50,000 lives each year.
It is currently impossible to determine if any of these parasite induced effects are the sole reason for cardiomyopathy, and in reality is it mostly likely a combination of autoimmunity and anti-parasite immunity and other factors that result in eventual cardiac death (1,2). The only cure for CCC is a heart transplant, and therefore discovering the pathogenesis of T. cruzi is of extreme importance. Until the exact mechanism of parasite induced autoimmunity is discovered, appropriate treatments will be impossible to find, and the T. cruzi killer will still be at large, claiming more than 50,000 lives each year.
Works cited:
1. Edecio, C. Bilate, A. Hyland, K. Fonseca, S. Kalil, J. Engman, D. “Induction of cardiac autoimmunity in Chagas heart disease: A case for molecular mimicry.” Autoimmunity, 39(1): 41-54. February 2006.
2. Engman, D. Leon, J. “Pathogenesis of Chagas heart disease: role of autoimmunity.”
Acta Tropica 8: 123–132. October 2002.
3. Bonney, K. Engman, D. "Chagas heart disease pathogenesis: One mechanism or many?" Current Molecular Medicine, 8, 510-518. 2008.
4. Wikepedia: molecular mimicry. http://en.wikipedia.org/wiki/Molecular_mimicry
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