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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Cell Microbiol. Author manuscript; available in PMC 2013 May 1.
Published in final edited form as:
PMCID: PMC3556388

Mechanisms of Trypanosoma cruzi persistence in Chagas disease


Trypanosoma cruzi infection leads to development of chronic Chagas disease. In this article, we provide an update on the current knowledge of the mechanisms employed by the parasite to gain entry into the host cells and establish persistent infection despite activation of a potent immune response by the host. Recent studies point to a number of T. cruzi molecules that interact with host cell receptors to promote parasite invasion of the diverse host cells. T. cruzi expresses an antioxidant system and thromboxane A2 to evade phagosomal oxidative assault and suppress the host’s ability to clear parasites. Additional studies suggest that besides cardiac and smooth muscle cells that are the major target of T. cruzi infection, adipocytes and adipose tissue serve as reservoirs from where T. cruzi can recrudesce and cause disease decades later. Further, T. cruzi employs at least four strategies to maintain a symbiotic-like relationship with the host, and ensure consistent supply of nutrients for its own survival and long-term persistence. Ongoing and future research will continue to help refining the models of T. cruzi invasion and persistence in diverse tissues and organs in the host.


The haemoflagellate Trypanosoma cruzi causes Chagas disease one of the important neglected tropical diseases of humankind. It is a cause of morbidity and mortality not only in endemic areas of Mexico, Central and South America but also among immigrants now residing in non-endemic areas of the world. Thus, the globalization of Chagas disease has brought new challenges and new opportunities in the understanding of the chronicity of the infection and the role of the immune system and of drug therapy in the modulation and or cure of this infection.

Trypanosoma cruzi has a complex life cycle involving mammalian hosts and insect vectors (Fig. 1). There are four distinct stages (blood-form trypomastigotes, intracellular amastigotes, epimastigotes and metacyclic trypomastigotes). In the natural life cycle, the insect vector ingests non-dividing blood-form trypomastigotes from a mammalian host, which then transform into epimastigotes that divide by binary fission in the gut of the vector. Approximately, 3–4 weeks later, epimastigotes convert to infective metacyclic trypomastigotes that move to hindgut of the vector. The transmission to the new host takes place when parasite-laden vector faeces contaminate and then enter the cells of the mucous membranes of the nose, oral cavity, conjunctiva or other vulnerable surfaces. In addition to vector-associated transmission, the other modes of transmission include vertical transmission from mother to child, contaminated food or drink, blood transfusion and organ transplantation. This obligate intracellular parasite chronically infects millions of people and up to 30% of the infected individuals ultimately develop clinically evident chronic cardiomyopathy or gastrointestinal disease (Rassi et al., 2010).

Fig. 1
Life cycle of Trypanosoma cruzi.

The transmission stage parasites, metacyclic trypomastigotes, cannot divide and must, therefore, penetrate mammalian host cells in order to continue the T. cruzi life cycle in the host. Evidence from experimental oral and conjunctivae infection studies (Giddings et al., 2006) suggest that T. cruzi initially infects and replicates within local tissues before dissemination in the bloodstream and infection of tissues at distal sites. During the acute stage of infection, there is an active invasion and intracellular replication cycle occurring in a variety of host tissues. The host immune response mounted to T. cruzi in the acute stage is effective in controlling parasite tissue load, but fails to clear infection, and parasites persist for decades in host tissues, often as asymptomatic infections. Little is known regarding the infection cycle of persistent parasites. Are the vast majority of normally replicating parasites continuously killed by host immune responses? Are the replication rates for intracellular amastigotes in chronic infection significantly slowed? Or is there a latent form of T. cruzi comparable with that of Mycobacterium tuberculosis or Toxoplasma gondii that has not been identified? Certainly, the detection of very low levels of circulating parasites in a significant fraction of chronically infected individuals (Gutierrez et al., 2009) suggests that the intracellular parasite life cycle is active, at least intermittently, and is the basis for recommending anti-parasitic therapy in the chronic indeterminate stage. Our focus in this review is to provide a commentary of the importance of parasite persistence in the context of Chagas disease.

T. cruzi invasion of the host cells

Mechanistic information regarding the T. cruzi invasion and replication cycle has been generated in cultured mammalian cells, and recently discussed (Caradonna and Burleigh, 2011). Briefly, to initiate entry into non-immune cells, T. cruzi trypomastigotes trigger Ca2+ flux in host cells that in turn stimulates transient depolymerization of the cortical actin cytoskeleton (Rodriguez et al., 1995) and promotes targeted exocytosis of lysosomes. The original model of trypomastigote invasion proposed that recruitment and fusion of host cell lysosomes at the parasite attachment site functioned to deliver membrane for the nascent vacuole. It was later demonstrated that the majority of parasites enter cells via plasma membrane invaginations to form vacuoles that subsequently fuse with early endosomes and lysosomes (Woolsey et al., 2003). Recently, a functional link between Ca2+-dependent lysosome exocytosis and T. cruzi entry via plasma membrane invaginations was established by demonstrating that release of lysosomal acid sphingomyelinase upon fusion of lysosomes with the plasma membrane converts sphingomyelin to ceramide, which facilitates membrane invaginations during T. cruzi invasion (Fernandes et al., 2011). In addition to triggering Ca2+ flux, trypomastigotes activate a number of signalling pathways in mammalian cells including class I phosphatidylinositol-3-kinases, which results in the local generation of PI(3,4,5)P3 on the membrane at the parasite entry site (Woolsey et al., 2003). Although required for efficient entry into non-phagocytic cells, the precise role(s) of PI-3 kinases in the invasion process are currently unknown. To promote Ca2+ signalling and invasion, trypomastigotes engage a number of host surface receptors including bradykinin receptor (B2R), endothelin receptors ETAR and ETBR (Andrade et al., 2012), low-density lipoprotein receptor (Nagajyothi et al., 2011) and cytokeratins, or may exert wounding of the plasma membrane (Fernandes et al., 2011). Much about the molecular interactions mediating host recognition by T. cruzi has yet to be defined; however, more general features may include the organization of cellular signalling receptors in membrane microdomains where a range of different receptors in different cell types could initiate similar signalling pathways involving intracellular Ca2+-transients and PI-3 kinase activation.

Amastigotes released along with trypomastigotes from infected cells also contribute to the parasite life cycle in the host where phagocytic cells are likely to play a prominent role. When the parasites enter a host cell they are first observed in a parasitophorous vacuole (Tanowitz et al., 1975) where they may be killed by the cytocidal mechanisms or may evade this onslaught and enter the cytoplasm. Regardless of the route of entry, parasites must traffic to the host cell lysosomal compartment in order to establish a productive intracellular infection. Targeting of parasites to lysosomes serves two functions. First, if endo/lysosomal fusion with the parasitophorous vacuole is prevented by inhibition of PI-3 kinase or by blocking actin dynamics with cytochalasin D (Woolsey and Burleigh, 2004), there is a failure to retain motile trypomastigotes by the cell. Second, the low pH environment of the lysosome provides the necessary conditions for T. cruzi-mediated disruption of the parasitophorous vacuole and release of parasites into the host cell cytoplasm (Ley et al., 1990).

Once in cytoplasm, the amastigotes multiply by binary fission. As obligate intracellular parasites, T. cruzi amastigotes clearly avail of the nutrient pool present in the host cell cytoplasm; however, little is currently known regarding the contribution of the host cell to supporting intracellular parasite growth and survival. As amastigotes accumulate, they sense that the life of their host cell is ending and transform to blood-form trypomastigotes. Parasites released from the host cell disseminate throughout the body via the lymphatics and the bloodstream to find new cells to invade. This process continues asynchronously for the life of the host. Although any nucleated mammalian cell can be parasitized by these organisms, cells of the reticuloendothelial, nervous and muscle systems, including the heart, appear to be favoured (Teixeira Vde et al., 1997; Viotti et al., 2006). In addition, recent observations demonstrate that adipocytes are readily invaded by trypomastigotes and may serve as a reservoir from which the infection may be reactivated (Combs et al., 2005).

Parasite persistence and chronic disease

Acute infection begins when the parasite actively proliferates in cells and continues to cause microvascular thickening, myocytolysis, and alteration of cardiac and enteric nerves. However, there are usually no cardiac or gastrointestinal manifestations associated with clinically evident acute infection. Approximately, 30–40% of infected individuals eventually develop chronic Chagas disease manifested by cardiomyopathy (Fig. 2), gastrointestinal involvement or both.

Fig. 2
A. Heart of a patient with chronic Chagasic cardiomyopathy. There is a 4-chamber enlargement of the heart. Note the apical aneurysm (arrow).

For many years there was a debate in the literature regarding the aetiology of chronic Chagas disease. It was the Tarleton laboratory (Zhang and Tarleton, 1999) that first conclusively demonstrated that the persistence of the parasite was a driving force in the perpetuation of the disease. It had always been assumed that chronic Chagas disease is associated with persistent infection with T. cruzi. For example, T. cruzi is frequently found in cardiac and smooth muscle cells in chronically infected experimental animals and humans (Viotti et al., 2006). Animals and humans that are chronically infected may also have evidence of parasites in the blood stream by PCR even though the parasite is not visible under the microscope (Gutierrez et al., 2009). Blood transfusion induced T. cruzi infection has been reported for many years including in non-endemic areas of the world necessitating the institution of screening of blood donors for the presence of T. cruzi antibody and if positive eliminating them from the blood donor pool (Castro, 2009). Congenital Chagas disease as a result of vertical transmission of the parasite from chronically infected mothers to the fetus is well documented in endemic areas of Latin America. It has now been reported to occur in the USA and the Europe among babies born to mothers with chronic Chagas disease leading to a recommendation that women of child-bearing age be screened for this infection before or early in pregnancy (Gascon et al., 2010). The administration of immunosuppressive agents to chronically infected individuals, sometimes in the setting of organ transplantation, may reactivate the infection requiring specific anti-T. cruzi therapy. It is now appreciated that in individuals with chronic Chagas disease who acquire HIV/AIDS, there may be reactivation of the T. cruzi infection (Diazgranados et al., 2009). Taken together there is substantial clinical evidence of persistence of T. cruzi infection.

The chronic indeterminate phase can last for decades or even a life-time and predominates in > 70% of the T. cruzi-infected individuals. It is not known why some individuals remain asymptomatic while others progress to a point where there is destruction of the heart and/or gastrointestinal tract. The strong immune response or autoimmune responses elicited by low-level tissue parasitism is the major factor contributing to the development of symptomatic disease. However, this is not the only factor in promoting disease as a low tissue parasite burden is also a major feature of the indeterminate phase of Chagas disease.

There are clinical implications of the persistence of T. cruzi infection in the humans. Individuals with end-stage heart disease or gastrointestinal disease albeit infected, are not candidates for specific anti-parasitic therapy and require supportive medical or surgical care. It is now recommended that individuals under 50 years of age who are asymptomatic but are seropositive for Chagas disease be offered anti-parasitic therapy with the available drugs (benznidazole or nifurtimox) (Viotti et al., 2006; Bern, 2011). The purpose of treatment is to prevent or ameliorate the chronic manifestations of this infection by reducing or eliminating the number of parasites. Whether this strategy will succeed is not known but is currently under investigation in clinical trials.

Mechanisms of parasite persistence

Suppression of phagocyte oxidative burst

Trypanosoma cruzi has developed mechanisms to evade innate immune mechanisms. Naive tissue-resident macrophages or activated macrophages, upon ingesting the parasite, activate NADPH oxidase and inducible nitric oxide synthase that produce superoxide (O2•−) and nitric oxide (NO) respectively. It is demonstrated that phagosomal O2•− and NO promote peroxynitrite (ONOO) mediated direct killing of T. cruzi in macrophages (Alvarez et al., 2011). Reactive oxygen species are critical regulators of the splenic inflammatory cell proliferation and cytokine responses during T. cruzi infection, and thereby also play an important role in the formation of adaptive immunity for parasite control (Dhiman and Garg, 2011). Recent studies suggest that T. cruzi utilizes an elegant antioxidant system to cope with the oxidative assault, ensuring its release from phagosome into host cell cytoplasm. Detailed discussion of the antioxidant system of T. cruzi has recently been presented in excellent reviews (Castro and Tomas, 2008; Piacenza et al., 2009a). Briefly, T. cruzi delivers reducing equivalents from NADPH to a variety of enzymatic detoxifying systems that utilize trypanothione [T(SH)2], glutathione, ascorbate or tryparedoxin (TXN) antioxidants. Proteomic studies suggest that iron-dependent superoxide dismutase (mitochondrial, detoxifies O2•−), trypanothione synthase (TcTS), TXN and members of tryparedoxin peroxidase family (TXNPx, neutralize ONOO and H2O2), are upregulated in metacyclic and blood-stage trypomastigotes and replicative amastigotes (Parodi-Talice et al., 2007). A direct correlation between expression level and/or activity of the cytosolic and mitochondrial isoforms of TXNPx and TcTS and virulence of T. cruzi isolates belonging to diverse phylogenetic lineages has been demonstrated in mice (Piacenza et al., 2009b) and humans (Diaz et al., 2011). Others have demonstrated by overexpression of mutant and wild-type form of TXNPx and TcTS that these enzymes are important for parasite survival, replication and differentiation (Pineyro et al., 2008). These studies conclude that T. cruzi utilizes its antioxidant system for a successful journey from macrophage invasion at the onset of infection to ensure dissemination to distant tissues and organs.

Besides surviving the acute oxidative assault of macrophages, antioxidant expression in diverse T. cruzi strains may also be linked to its ability to establish chronic infection in other cells and tissues in the host. In vitro studies in human and murine cardiac myocytes (Ba et al., 2010) and in vivo studies in experimental animals (Wen and Garg, 2010) have demonstrated that exposure to T. cruzi altered mitochondrial membrane pore transition potential and electron gradient across the respiratory chain that led to leakage of electrons to O2 and increased O2•− formation in infected cardiomyocytes and heart [reviewed in (Gupta et al., 2009)]. These ROS can promote direct parasite killing, and mitochondrial release of ROS and other molecules (e.g. cytochrome c) are known stimuli to activate apoptosis pathway for removal of damaged cells (van Empel et al., 2005). Conceivably, T. cruzi isolates expressing higher levels of antioxidants have the ability to scavenge intracellular (mitochondrial) ROS and prevent cell death and normal homeostatic clearance of invaded cells by apoptosis pathways, thereby ensuring a supply of nutrients for its long-term survival in the host.


The prostaglandins, together with the thromboxanes and prostacyclins, form the prostanoid class of fatty acid derivatives, and a subclass of eicosanoids. Early studies have shown that activated platelets, the major source of host thromboxane A2 (TXA2), have a direct anti-trypanosomal activity, yet, during the infection there is thrombocytopenia, increased platelet adherence, increased platelet aggregation that likely limits the anti-parasitic action of these cells (Tanowitz et al., 1990). Later, a novel discovery was made that demonstrated the vast majority of the vasoactive and proinflammatory TXA2 found in the plasma of T. cruzi-infected mice is actually parasite-derived (Ashton et al., 2007). The release into the bloodstream of TXA2 appears to aid in the survival of acutely infected mice and in the transition to the chronic state. This was evidenced by the observation that preventing host response to parasite-derived TXA2 augmented death and parasitaemia. TXA2 regulates vasospasm, thrombosis, vascular permeability and endothelial cell dysfunction during acute infection. Additionally, TXA2 displays immunosuppressive properties with the wild-type mice displaying minimal pathology while the TXA2 receptor null mice display increase in myocardial inflammation and tissue parasitism. The host TXA2 signalling may act as a potential quorum-sensing mechanism for the parasite regulating intracellular amastigote proliferation, thus preventing overwhelming of the host during acute infection and allowing the transition into a chronic persistent infectious state. Thus, it is clear that TXA2 plays an important role in acute murine T. cruzi infection and the role of parasite-derived mediators have been under-appreciated in disease pathogenesis and in the transition to the chronic persistent state. Ongoing studies in several laboratories continue to examine the role of parasite- and host-prostaglandin pathways in the pathogenesis of Chagas disease.

Survival and hiding in adipose tissue

Trypanosoma cruzi infection of adipose tissue was described in detail in 1970 (Shoemaker et al., 1970). It was 25 years later, when the systematic analysis of the metabolic consequences of T. cruzi infection clearly established the functional significance of parasitism of adipose tissue and the adipocytes in a mouse model (Combs et al., 2005). When mice were infected with T. cruzi, the plasma levels of adiponectin, a physiologically important protein synthesized by adipocytes, were significantly reduced, and there was a concomitant reduction in the expression of PPAR-γ. Importantly, both adiponectin and PPAR-γ negatively regulate inflammation, and reduced levels of adiponectin are often associated with insulin resistance, hyperglycaemia and obesity.

As early as 15 days after T. cruzi (Brazil strain) infection of mice, there is a significant parasite load in both brown and white adipose tissue as compared with other organs such the heart and spleen (Nagajyothi et al., 2012). This is accompanied by a significant reduction in fat mass and fat content and decrease in the average size of adipocytes and influx of macrophages into adipose tissue of infected mice. Immunoblot analysis reveals an increase in lipolysis although apoptosis and necrosis may also be involved.

Thirty days post infection, when significant systemic inflammation prevails, acute-phase reactants, such as α-1 acid glycoprotein and SAA3 are upregulated in adipose tissue. The levels of resistin, another adipocyte-specific secretory factor with insulin-desensitizing properties, remain unchanged in adipose tissue obtained from T. cruzi-infected mice. The expression of proinflammatory cytokines (TNF-α, IL-1β, IFN-γ), chemokines and toll-like receptors in adipose tissue is elevated in acutely infected mice (Combs et al., 2005). During the chronic phase of murine infection, adipose tissue displays persistence of both macrophages and parasites. These data suggest that adipose tissue is an early sensor as well as a target of T. cruzi infection and represents a chronic reservoir from which infection can recrudesce during periods of drug-induced or physiological immunosuppression as well as lipoatrophy-associated with HIV/AIDS.

Others have suggested that the chronic/persistent parasitism of adipose tissue by T. cruzi could create a ‘low-grade’ chronic inflammatory state similar to what is observed in morbid obesity (Ferrante, 2007). The observation that a local lipolysis-induced increase in fatty acids in adipose tissue led to an increased infiltration of macrophages (Kosteli et al., 2010) provides a potential explanation for the long-term effects observed on some fat pads after acute T. cruzi infection. The presence of parasites within chronically infected fat pads may lead to insulin resistance, causing increased lipolysis with chronically elevated local free fatty acid levels that in turn trigger an increased infiltration of macrophages. As adipose tissue is composed of many cell types, direct evidence of the consequences of infection on cultured adipocytes provides important support for an inflammatory phenotype (Nagajyothi et al., 2008). T. cruzi infection of cultured adipocytes results in increased expression of PI3 kinase and the activation of protein kinase B (AKT), strongly suggesting the induction of the insulin/IGF-1 receptor pathway. This is an unexpected observation because the upregulation of proinflammatory pathways is usually associated with a downregulation of the insulin signal transduction pathway (Ferrante, 2007). Thus, T. cruzi infection of cultured adipocytes as well as adipose tissue in vivo results in alterations of several important pathways early in infection that persist well into the chronic phase. T. cruzi has a high affinity for lipoproteins and alter serum lipoprotein levels during infection. Lipoprotein binding also facilitates the invasion of cells by the parasite and thus, could explain, in part, the persistence of the parasite in adipose tissue and adipocytes.

The viewpoint that adipose tissue and adipocytes are both targets of infection and a long-term storage site from which infection can arise later in life under circumstances of immunosuppression has recently gained increased acceptance as it was demonstrated that Rickettsia prowazekii, the causative agent of Brill-Zinsser Disease, lives in adipocytes which serve as a reservoir from which the infection can recrudesce and cause disease decades later (Bechah et al., 2010). The persistence of T. cruzi over 300 days post infection is noted in adipose tissue of infected mice (Combs et al., 2005). Recently, it was confirmed that in adipose tissue of chronic Chagasic patients, there is persistence of the parasite (Ferreira et al., 2011).

Parasite-derived cell protective mechanisms

Tissue parasitism contributes to disease progression and may be considered a double-edged sword. Cellular signalling elicited by parasitism assists in the repair of the host tissues injured by infection, which could explain the lack of pathology and symptoms in a majority of patients during the acute and indeterminate phases of the disease. However, tissue parasitism elicits strong immune responses resulting in fibrosis and tissue dysfunction. Thus, clinical disease associated with pathological changes would occur despite the protective mechanisms triggered by the parasite. The anti-apoptotic nature of T. cruzi in cardiomyocytes via NF-κB/Bcl-2-mediated inhibition of caspase activity is described, although no specific parasite factor was identified (Petersen et al., 2006). In later studies, at least four cell protective agents and activities in T. cruzi were identified that support the hypothesis that the parasite maintains a symbiotic-like relationship with the host leading to parasite persistence. Penetrin, a heparin-binding protein on the surface of T. cruzi, allows the parasite to penetrate epithelial cells. By analogy with host growth factors such as fibroblast growth factor, which promotes tissue repair by binding to heparin-like or heparan sulfate structures on host cells, penetrin could induce host-cell survival in T. cruzi-infected sites (Ortega-Barria and Pereira, 1991). Similarly, a T. cruzi surface protein that binds and activates the signalling receptor of transforming growth factor β promotes both parasite invasion of cells and secretion of extracellular matrix proteins, which is essential for tissue repair (Waghabi et al., 2009). The third agent on T. cruzi with tissue repair potential is a mimic of the glial cell derived neurotropic factor that protects and promotes neuron differentiation (Lu and PereiraPerrin, 2008). The fourth and best-characterized growth factor mimetic is the surface protein originally identified as neuraminidase/trans-sialidase (Alves and Colli, 2008). The neuraminidase/ trans-sialidase binds and activates tyrosine kinase receptors TrkA and TrkC (Weinkauf and Pereiraperrin, 2009), normally signalled by nerve growth factor (NGF) and neurotrophin-3 to regulate differentiation, survival and other important functions of neuron (Fig. 3). Neuraminidase/trans-sialidase also serves as a parasite-derived neurotropic factor and promotes cell survival actions by directly interacting with and activating Akt kinase (Chuenkova and PereiraPerrin, 2009), an enzyme essential for various types of tissue repair mechanisms. Microarray studies reveal that T. cruzi infection of cultured cardiac myocytes upregulates the expression of NGF (Manque et al., 2011); although it is not clear how T. cruzi increases production of NGF. This observation suggests that infection-induced release of NGF triggers survival paracrine signalling through TrkA/TrkC, in addition to neuraminidase/trans-sialidase-mediated Trk activation. Thus, T. cruzi may participate in the tissue repair mechanism at infection sites through the production of growth factor mimetics. These mimetics likely help maintain a balance between tissue damage and repair and contribute to the absence of cardiac and gastrointestinal abnormalities and survival of patients with acute Chagas disease and the majority of patients who stay in the indeterminate phase for prolonged periods of time (Rassi et al., 2010). This hypothesis is consistent with the observations of neuronal loss in chagasic heart and the gastrointestinal tract, which occurs predominantly during the acute infection and remains at a steady state in the indeterminate phase (Chuenkova and Pereiraperrin, 2011). Autonomic dysfunction due to decreased innervations can be detected in patients with the indeterminate form of the disease, the patients are nevertheless asymptomatic and without pathology as indicated by electrocardiogram and radiological examinations. Others have provided evidence of neuroprotection in Chagas disease. It was shown that although the number of ganglia in patients with the indeterminate form is lower than in age-matched non-chagasic individuals, the average number of both cardiac and gastrointestinal ganglia actually increased with the age of chagasic patients (Meciano Filho et al., 1995). T. cruzi-infected animals showed neurite development, axon regeneration, and sprouting in the heart and colon (Losavio et al., 1989). Recent studies provide evidence of neuroregeneration (based on GAP-43, a marker of differentiating neurons) in the dilated colons of chagasic patients (da Silveira et al., 2008).

Fig. 3
Parasite-derived neurotropic factor (PDNF) regulation of host cell signalling during T. cruzi infection. T. cruzi binding to Trk receptors mediated by PDNF activates Trk-dependent signalling of MAPK/Erk1/2 and PI3K/Akt, resulting in phosphorylation of ...

Therapy and immunity/autoimmunity

Several studies demonstrate that despite a competent immune system and the generation of a robust CD8+T cells response, T. cruzi infection whether in experimental animals or humans, does not completely resolve (Padilla et al., 2009). The infection persists most notably in adipose tissue and muscle including cardiac muscle. The reason for the persistence in these particular tissues is not fully understood, but it has been suggested that the parasite uses fatty acids, available in abundance in adipose and muscle tissues, as source of energy. Treatment of T. cruzi-infected mice with benznidazole resulted in a complete clearance of the parasite and a shift in the T. cruzi-specific CD8+T cells to protective central memory phenotype (Bustamante et al., 2008). It is not clear if presence of central memory CD8+T cells is linked to cure of infection in humans and whether change in CD8+ T-cell phenotype provides a better protection from new infections. This area of research is currently pursued in several research laboratories.

The presence of a positive serology in chronically infected animals and humans is also considered a strong indication of the persistence of the parasites. Several compounds have the ability to clear blood trypomastigotes during acute infection. In humans and experimental animals treated early in the course of infection, antibody titres have either never become positive or revert from positive to negative. Seropositive children and young adults have been reported to seroconvert following therapy and it is believed that this correlates with complete cure (Escriba et al., 2009); although there are no consistent and verifiable markers of cure. In addition, there is no direct evidence that the intensity of the parasitism directly correlates with pathophysiological alterations in organs such as the heart.

The role of autoimmunity in the perpetuation of the disease has been the topic of much investigation over the years. In some humans and experimental animal models, both humoral and cell-mediated cardiac-specific autoimmunity develops during T. cruzi infection. Importantly, benznidazole therapy results in a reduction of the parasite load in the heart and in the intensity of the myocardial inflammation. It has been suggested that myosin-specific autoimmunity may not be very important in the pathogenesis of inflammation in acute infection and that parasite-specific cell-mediated immunity is an important mechanism in the pathogenesis of myocarditis and persistence of this infection (Leon et al., 2003). Others have shown a link between the level of the parasite and the presence of autoimmunity (Hyland et al., 2007), and suggested that elimination of the parasite may result in the reduction or elimination of autoimmunity during chronic infection.


Trypanosoma cruzi utilizes host cell surface receptors to gain entry and exploits the innate immune responses by expression of antioxidants and TXA2 to survive and establish infection in the host. The realization that T. cruzi hides in adipose tissue and can promote both destructive and regenerative processes in the infected host suggest that the parasite is equipped with multiple tools to establish a long-term relationship with the infected host. These studies provide future therapeutic opportunities to prevent parasite dissemination and progression from asymptomatic to pathological disease state.


We apologize to colleagues whose work could not be cited because of space limitations. The work in authors’ laboratories is supported in part by National Institutes of Health grants AI076248, HL73732, AI06538 (H.B.T.), DK55758, CA112023, DK086629 (P.E.S.), 2AI054578, HL088230, HL094802 (N.J.G.), and AI090366 (B.B.), CNPq and FAPEMIG grants (F.S.M.), DRTC, AECOM grant (H.B.T.), and an American Heart Association grant (S.M.).


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