# Trypanosoma cruzi Infection and Host Lipid Metabolism

Authors: Qianqian Miao; Momar Ndao
Journal: Mediators of Inflammation
 (2014)

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## Abstract

Trypanosoma cruzi is the causative agent of Chagas disease. Approximately 8 million people are thought to be affected worldwide. Several players in host lipid metabolism have been implicated in T. cruzi-host interactions in recent research, including macrophages, adipocytes, low density lipoprotein (LDL), low density lipoprotein receptor (LDLR), and high density lipoprotein (HDL). All of these factors are required to maintain host lipid homeostasis and are intricately connected via several metabolic pathways. We reviewed the interaction of T. cruzi with each of the relevant host components, in order to further understand the roles of host lipid metabolism in T. cruzi infection. This review sheds light on the potential impact of T. cruzi infection on the status of host lipid homeostasis.


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## Body

## 1. Introduction

Trypanosoma cruzi (T. cruzi) is the etiological agent of Chagas disease (CD). It is estimated that 8 million people are infected worldwide [1]. In the endemic area of South and Central America, CD is transmitted through contact with the feces of the triatomine bug (the kissing bug). When taking a blood meal from a human, the bug defecates on the skin whereT. cruzi can enter the wound or the mucosal membrane by scratching. Effective vector-control programs have greatly decreased disease transmission in these areas [2, 3]. However, CD was brought to North America, Europe, and Asia by infected individuals, through migration in recent years. In nonendemic area, CD is transmitted through blood transfusion, organ transplantation, and congenital transmission [4].During theT. cruziinfection process, the parasite interacts with a wide range of host immunological and metabolic factors. In the past decade, special attention was given to the close relationship betweenT. cruziinfection and host lipid metabolism. Several research groups have uncovered the interaction betweenT. cruziand players in the host cholesterol transport and storage system such as macrophage [5–7], adipocytes [8], low density lipoprotein (LDL), and high density lipoprotein (HDL) [9–11]. The molecular landscape and impact of these relationships inT. cruziinfection and pathogenesis, as well as host immunological responses and inflammatory reactions, will be reviewed in this paper.There are three stages in CD progression: acute, indeterminate, and chronic. Although the majority of infected individuals are asymptomatic while carrying the life-long infection, some develop severe symptoms upon infection. During the acute stage, infected individuals may develop unspecific symptoms such as fever, nausea, diarrhea, and rash, as well as severe symptoms such as a raised inflammatory lesion at the site of parasite entry (chagoma), unilateral periorbital edema (Romana’s sign), lymphadenopathy, and hepatosplenomegaly [12]. The majority of patients survive the acute stage and enter the prolonged indeterminate stage without overt symptoms of disease, which lasts for life. However, thirty percent of patients develop chronic CD, which includes grave symptoms such as megaesophagus, megacolon, and chronic heart disease [13].T. cruzihas a complex life cycle and undergoes several transformations during the infection process. The parasite exists mainly in its epimastigote form in the triatomine vector. It transforms into metacyclic trypomastigote in the hind gut of the vector which is then defecated to infect human host. Once in the host, the metacyclic form infects a wide range of phagocytic (i.e., monocytes, neutrophils, mast cells, and macrophages) and nonphagocytic cells (i.e., epithelial cells, endothelial cells, fibroblasts, and mesenchymal cells). Upon infection, trypomastigotes transform into intracellular amastigotes and divide by binary fission. Once the division process is complete, amastigotes transform back into blood trypomastigotes which escape the cell to infect neighbouring cells or enter the blood circulation [14].


## 2.T. cruzi Infection and Macrophage Lipid Bodies

Lipid bodies (LB), also named lipid droplets or adiposomes, are lipid-rich organelles existing in almost all organisms. Unlike other organelles, lipid bodies are uniquely surrounded by a monolayer of phospholipids [15]. The core of the lipid body is rich in neutral lipids, mainly triacylglycerol and sterol esters, as well as other putative membranous structures [15]. Historically, lipid bodies were thought to function in neutral lipid storage and transport; however, recent research has uncovered their importance in regulation of host immune responses. Lipid bodies are involved in the formation of paracrine mediator eicosanoids in cells involved in inflammatory processes [16, 17]. The number of lipid bodies in leukocytes increases in response to a variety of inflammatory conditions, such as atherosclerosis and mycobacterial infections [18, 19].During acuteT. cruziinfection, host macrophages are strongly activated and will inhibit parasite replication [20]. It has been demonstrated that activated murine macrophages are capable of killing the parasitesin vitro [5–7]. The macrophage inhibition of parasite replication also correlated positively with increases in the oxidative burst activity [21], tumor necrosis factor-alpha production (TNF-α) [7], and nitric oxide secretion [22]. Macrophages from more resistant C57/BL6 mice strain also secreted higher TNF-α in thein vivo experiments compared to macrophages from the susceptible strains, such as C3H and BALB [23]. In macrophage-depletedT. cruziinfected rats, myocardial parasite load as well as blood parasitemia was significantly increased compared to control [24]. When irradiate rats, which have very low numbers of T and B lymphocytes, were treated with recombinant Interferon-γ (IFN-γ), which classically activates host macrophages,T. cruziparasite load was significantly reduced [25]. These findings demonstrated the importance of macrophage in the clearance of parasites. However, the roles of macrophage inT. cruziinfection may not be as simple as previously thought. Certain features of macrophage activation may aid in parasite survival in the host. Melo showed that, during acuteT. cruziinfection, there is a prominent increase in the number of lipid bodies in macrophages [26]. This increase in lipid body formation correlated with increased parasite loadin vivo [27]. It was further demonstrated that the induction of lipid body formation duringT. cruziinfection was Toll-like receptor (TLR-2) dependent and was enhanced by the uptake of apoptotic cells, which causes macrophage to interact with αvβ3 integrin and activates TGF-β-dependent lipid body formation [27, 28]. Increased levels of TGF-β are known to cause phagocytic cells to become permissive toT. cruziinfection [29, 30] (Figure 1(a)).Figure 1
Trypanosoma cruziinteracting with various components of host lipid metabolism. (a)T. cruziinfects macrophage and activates TLR-2 signaling which causes the increased lipid bodies (LB) number and altered LB morphology. This effect is further enhanced by macrophage uptake of apoptotic cells. Increased LB number causes increased eicosanoid production, which leads to upregulation of TGF-β and increased cell susceptibility toT. cruziinfection. (b)T. cruziuses adipocytes as a reservoir for chronic infection.T. cruziinfection causes adipocytes to display an inflammatory phenotype, upregulating cytokines such as IL-1β, IFN-γ, TNF-α, CCL2, CXCL10, and CCL5. TLR-2 and 9, which are essential toT. cruziinfection, are also upregulated. The infection also causes downregulation of adiponectin secretion via PPAR-γ expression. (c) Host LDL inhibitsT. cruzi trans-sialidase and increasesT. cruziinfectionin vitro. LDL can be taken up by the liver and extrahepatic cells by LDLR. It is unknown whether LDL-LDLR interaction plays a role inT. cruziinfection. (d)T. cruzienters host cell via LDLR. LDL-R activation leads to lysosomal recruitment to parasitophorous vacuole and parasite internalization. (e) HDL inhibitsT. cruzi trans-sialidase activity and increasesT. cruziinfectionin vitro. HDL is uptaken by host cells via receptor mediated interaction with SR-BI. Whether this interaction can be utilized byT. cruzicell entry process is not known. (f) Apo A-I in the HDL complex is cleaved by the major cysteine protease ofT. cruzi,cruzipain. Cruzipain andtrans-sialidase are similarly expressed and located during different life stages ofT. cruzi. It is possible that HDL is bound to the surface ofT. cruzitrypomastigotes bytrans-sialidase and is cleaved by cruzipain in the acidic environment in the parasitophorous vacuole. Host cholesterol transport by VLDL, LDL, and HDL is indicated in red arrows. Host VLDL and lipid-poor nascent HDL particles are produced in the liver. By effluxing cholesterol, host VLDL transforms to become LDL and nascent HDL becomes mature HDL. LDL particles can be oxidized and uptaken by macrophage. Lipid-laden macrophages are termed foam cells and are major contributors in host atherosclerosis development. HDL effluxes cholesterol from peripheral tissue via the action of ABCA1 or ABCG1 and returns cholesterol to hepatic tissues for storage or excretion.Increased lipid body formation also led to increased eicosanoid prostaglandinE2  (PGE2) production in inflammatory macrophages. Prostaglandins are known to inhibit TNF-α and IFN-γ production, while enhancing TGF-β secretion [31–33]. Release of prostaglandins reduces macrophage trypanocidal function [31, 34]. Although the impact of PGE2 release inT. cruziinfection is contradictory, the release of PGE2 was correlated in resistance against certain strains ofT. cruziinfection [35]. In addition, treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX) inhibitors was able to modulate lipid body formation and decrease PGE2 production, which led to decreased parasite growth in macrophages [27, 36].Furthermore, these newly formed lipid bodies also varied significantly in size and light density, which indicated the structural participation of these organelles in immune responses toT. cruziinfection. The structural alterations of LB in macrophages may be related to the different lipid compositions in the organelle, stage of new LB formation, or fluctuation of the arachidonate production and concentration [37]. Ultrastructural investigation revealed that the newly formed lipid bodies are localized in close proximity to macrophage phagolysosomes or even within these structures. This suggests that lipid bodies may interact with the phagolysosomes during acuteT. cruziinfection [38]. Lipid bodies are known to provide nutrients to intracellular parasites such asLeishmania chagasi,which are located in the phagolysosome [39]. The relationship between lipid body and phagolysosome can also be beneficial to the host. As reviewed by Melo et al., lipids recruited during lipid body formation, such as arachidonic acid (AA), are able to activate actin assembly, phagosome-lysosome fusion, and phagosome maturation [40, 41]. In addition, these lipids can activate phagosomal nicotinamide adenine dinucleotide phosphate- (NADPH-) oxidase, which leads to pathogen elimination [42]. The implication of the close localization of lipid bodies and phagolysosome inT. cruziinfected macrophages needs to be further investigated.


## 3.T. cruzi Infection and Host Adipose Tissue

Adipose tissue is one of the largest organs in the host. It is comprised of a wide range of cell types including adipocytes, pericytes, monocytes, macrophages, and endothelial cells [43]. The function of adipose tissue has long been considered to be energy storage. More than 95% of adipocyte cell mass is lipid droplets where triglycerides and cholesterol esters are stored [44]; however, it was recently uncovered that the functions of adipose tissue include not only energy storage, but also metabolic regulation, neuroendocrine, and immune regulations [45]. Adipose tissue is home to a variety of adipokines, such as adiponectin [46], leptin [47], and resistin [48], which are prominent regulators of lipid homeostasis and immunological functions.Recently, metabolic dysfunction was linked to CD pathogenesis by the observation that there are greater incidences of diabetes inT. cruziinfected individuals [49]. Later research showed decreased insulin level and dysregulated glucose responses among CD patients [50, 51], which further demonstrated the dysregulation of energy metabolism in these patients. It was also shown that chemically induced diabetic mice as well as genetically predisposed db/db diabetic mice with defective leptin receptors had higher parasitemia and mortality afterT. cruziinfection, which suggests that the dysregulation of host metabolism may be beneficial to parasitic survival in the host [52].Adipocytes are the key cell type in metabolic dysregulations such as diabetes [53]. The role of adipocytes in CD pathogenesis was therefore investigated. Mice infected withT. cruzishowed symptoms of hypoglycemia during the acute stage of infection; however, insulin sensitivity was unaltered [54]. Levels of adiponectin and leptin were significantly reduced inT. cruziinfected mice, which further suggest the altered state of glucose regulation and possible adipocyte involvement in disease progression [54]. Adiponectin is the only adipokine secreted exclusively by adipocytes and is strongly associated with insulin resistance and hyperglycemia. High parasite load was detected in the adipose tissue at the chronic stage, 300 days postinfection, as measured by quantitative polymerase chain reaction (qPCR). Decreased levels of adiponectin in the plasma and adipose tissue of infected mice were also observed during the chronic stage. Microscopic investigation revealed the preferred localization ofT. cruziin the brown fat of adipose tissue, where lipid bodies are higher in number and smaller in size compared to white adipocytes. These findings suggest that adipose tissues may serve as the parasitic reservoir during chronic infection and adipokine synthesis was disrupted possibly due to the infection [54]. Observations thatT. cruziparasite is present in the adipose tissue biopsy of chronically infected human patients have further confirmed the finding that adipose tissue is the reservoir of chronicT. cruziinfection [55]. Several follow-up studies have also shown the susceptible nature of adipocytes toT. cruziinfection [8, 56].In vitro infection of cultured adipocytes withT. cruzirevealed that a panel of proinflammatory cytokines was upregulated; these include IL-1β, IFN-γ, TNF-α, chemokine ligand (CCL2), CCL5, and C-X-C motif chemokine 10 (CXCL10) The expressions of TLR-2 and 9 are also upregulated [8]. Other pathways, such as notch, extracellular signaling-regulated kinases (ERK), and phosphoinositide-3-kinases (PI3K), were also activated. It was shown that both ERK and PI3K pathways were activated uponT. cruzi infection [57, 58]. Furthermore, PPAR-γ is highly expressed in adipose tissue and, along with adiponectin, exerts anti-inflammatory effect [59]. Levels of peroxisome proliferator-activated receptor (PPAR-γ) were decreased in the infected cells, which may have led to the decreased secretion of adiponectin and increased inflammatory reactions. These findings suggest that infection of adipocytes withT. cruzimay contribute to the systemic proinflammatory immune responses as well as metabolic dysregulation [8] (Figure 1(b)).In summary, recent research has revealed that adipose tissue may be the most important reservoir forT. cruzichronic infection and these infected adipocytes display a proinflammatory phenotype. Altered activation profile of several kinase pathways in adipose tissues may also contribute to host metabolic dysregulation. However, questions remain unanswered. It is clear that chronicT. cruziinfection displays tissue tropism; however the evolutionary benefits ofT. cruziresiding in adipocytes are unknown.T. cruzimay utilize the lipid stores within the adipocytes for its multiplication and survival. It is also possible thatT. cruzichooses adipocytes for its prolonged life-span. In addition, the specific mechanism ofT. cruzi-adipocyte interaction is unknown. Further research is needed to unravel the biological processes behind the relationship betweenT. cruziand adipocytes.


## 4.T. cruzi Infection and Host Cholesterol Transport Pathways

T. cruziglycoprotein 85 (gp85)/trans-sialidase is similar to that of viral and bacterial neuraminidases. However, unlike other neuraminidases, upon hydrolysis of α-linked sialic acid from glycoconjugates on cell surfaces,T. cruzi trans-sialidase transfers the sialic acid onto parasitic receptors [60]. The expression and activity oftrans-sialidase are developmentally regulated and are present at about the same extent in epimastigotes and trypomastigotes. Minimaltrans-sialidase activity was detected in amastigotes [61].Trans-Sialidase is known to be involved in trypomastigote cell adhesion and invasion process by interacting with a wide range of ligands, such as laminin, fibronectin, and collagen [62–65]. Inhibition ofT. cruzi trans-sialidase by specific antibodies led to the increased rate of infection [66].Cholesterol transport chains are the major components of maintaining host lipid homeostasis and lipoproteins are essential players in these pathways. Lipoproteins are categorized based on their density and protein content into high density lipoproteins (HDL, density 1.603–1.210), low density lipoproteins (LDL, density 1.019–1.603), intermediate density lipoproteins (IDL, density 1.006–1.019), very low density lipoproteins (VLDL, density 0.95–1.006), and chylomicrons (density < 0.95). All lipoproteins allow the transport of hydrophobic lipid contents, such as cholesterol, triglycerides, and phospholipids, within the hydrophilic blood circulation system.LDL is characterized by the presence of a single copy of apolipoprotein B-100 (Apo B-100) molecule on its surface. It is generated from liver-derived VLDL by a process mediated by lipoprotein lipase and hepatic lipase as well as lipid exchange proteins [67, 68]. LDL has been shown to be a potent inhibitor ofT. cruzi trans-sialidase and enhances the infection of human fibroblastsin vitroin a dose-dependent manner [10]. The enhanced infection rate seen upon the addition of LDLin vitro is comparable to that of the enhancement caused bytrans-sialidase inhibition [10]. LDL particles were seen covering the parasite cellular surface ofT. cruzitrypomastigotes, but not amastigotes [69]. The localization of LDL particles correlates withtrans-sialidase localization on the parasite surface and suggests that LDL may directly inhibitT. cruzisurfacetrans-sialidase to enhance rate of infection (Figure 1(c)). However, the exact molecular mechanism of this interaction has yet been demonstrated.Previous reports have also shown that LDL can be endocytosed byT. cruzi epimastigotes [69]. Gold-labelled LDL particles were found within flagellar pockets. Immunoelectron microscopy showed thattrans-sialidase expression is most concentrated in the flagellar pocket region, which suggested that despite LDL inhibition ofT. cruzi trans-sialidase,trans-sialidase may also facilitate LDL endocytosis by the parasite [70]. Reservosomes are the site of accumulated endocytosed proteins and lipids inT. cruzi. This organelle in the parasite provides support for metacyclogenesis from epimastigotes to trypomastigotes [71, 72]. LDL particles were also found in theT. cruzimembrane enclosed vesicles and reservosome within the parasite. LDL may be stored and processed in the reservosome for usage during this transformation and infection process [73]. Similar process of LDL uptake was also demonstrated inLeishmania amazonensis, a parasite closely related toT. cruziin the Trypanosomatidae family [74].Another important molecule in the LDL metabolic cycle is the LDL receptor (LDLR). LDLR plays an essential role in the internalization of circulating LDL in the host liver and peripheral cells. A significant amount of cholesterol is delivered to these organs via the interaction of LDL-LDLR [75]. Approximately 50% of LDL is removed at the liver [76]. LDLR also facilitates the endocytosis of a variety of other ligands, such as proteinases and proteinase-inhibitor complexes, as well as interacting with cytoplasmic adaptor proteins which have signaling transduction functions [77]. The expression of LDLR by the host cell is regulated by a wide range of lipid metabolic and immune regulatory stimuli, such as intracellular cholesterol level, oxysterols, various growth factors, and cytokines [78, 79]. Ruan et al.  demonstrated that, in human mesangial cells, increased levels of TNF-α, TGF-β, and IL1-β caused increased transcription of LDLR [80]. LDLR was previously shown to be a potential host receptor for Hepatitis C virus (HCV) and other flaviviridae viruses [81, 82]. However, this direct interaction was not documented in parasitic infections until recently.TheT. cruzi parasite specifically binds to LDLR during the infection process [83]. Activation of LDLR facilitates the recruitment of lysosomes to the parasitophorous vacuole, which leads to the internalization ofT. cruziinto the cytoplasm. Disruption of LDLR by genetic knockout resulted in 62% reduction inT. cruziinfection, which suggests LDLR is essential forT. cruzicell invasion process (Figure 1(c)). Furthermore, upregulation of LDLR expression was also seen in the heart ofT. cruziinfected CD1 mice [83]. Moreover, inToxoplasma gondii infection, LDLR functions to uptake LDL particles and support intracellular parasite growth [84]. It is recently demonstrated thatT. cruziinteraction with LDL receptor leads to the increased accumulation of LDL-cholesterol in host tissue in both acute and chronic CD [85].Alterations in the micro- and macrovascular circulations and atherosclerosis-like symptoms are commonly seen in cardiomyopathic patients [86, 87]. Bestetti et al. reported thatT. cruziinfection in combination with a high cholesterol diet can induce early symptoms of atherosclerosis in mice [88, 89]. LDL and LDLR were implicated extensively in atherosclerosis pathology and progression. It is known that LDL particles are transported across the endothelium and become trapped in the matrix of arterial wall cells, which leads to the production of highly cytotoxic oxidized LDL and subsequently activates inflammatory pathways, such as NFκB [90]. The interaction ofT. cruziwith LDLR may increase host susceptibility to atherosclerosis and arterial pathology.In addition to the parasite interaction with LDL and LDLR,T. cruzialso interacts with HDL (originally named cruzin inT. cruziresearch [91]), the major component of the reverse cholesterol transport pathway. HDL is a complex, multistructured particle consisting of two layers of phospholipids that are held together by two molecules of apolipoprotein A-I (Apo A-I). The main function of HDL is to remove excess cholesterol from peripheral tissues and return it to the liver for storage and excretion [92]. Other functions of HDL also include inhibiting LDL oxidation, platelet aggregation and coagulations, and endothelial inflammation, as well as promoting endothelial nitric oxide production and prostacyclin bioavailability [93, 94].Similar to LDL-T. cruziinteraction, HDL was shown to bind to and inhibitT. cruzitrypomastigotestrans-sialidase activity [11, 95]. Interestingly, this interaction is specific forT. cruziand was not found inTrypanosoma rangeli,an infectious agent nonpathogenic to human hosts.T. cruziandT. rangelioverlap geographically, share antigenic protein, and are able to infect the same triatominae vector and vertebrate hosts. HDL inhibition ofT. cruzi trans-sialidase functions in a dose-dependent manner through a reversible noncompetitive mechanism [95]. Maximum association between HDL andT. cruzi trans-sialidase occurs in less than 5 min and lasts more than 120 min [11]. More importantly, HDL inhibition ofT. cruzi trans-sialidase enhances parasite infectionin vitro [10]. Recently, Weizong et al. have discovered similar interaction between Apo A-I and Dengue virus. The research group showed that Apo A-I is associated with the virus particles and preincubation of dengue virus with HDL enhances viral infection through a scavenger receptor-BI- (SR-BI-) mediated mechanism [96]. These findings may also provide a possible mechanism for the enhancement ofT. cruziinfection by HDL (Figure 1(e)). Furthermore, our research has shown that, during the intracellular amastigote stage of infection, groups infected in the presence of HDL had lower number of intracellular parasites than groups without HDL (Q. Miao & M. Ndao, personal communication). It is possible that HDL inhibition ofT. cruzi trans-sialidase led to the decreased rate of trypomastigotes escaping from the parasitophorous vacuole and delaying the process of trypomastigote transformation [97].In theT. cruziepimastigote form, HDL may also be endocytosed and function as nutritional supply [10]. HDL endocytosis was first observed inTrypanosoma brucei brucei(T. b. brucei).T. brucei (African trypanosome) is closely related toT. cruzi(American trypanosome) in evolutionary lineage and shares a high level of biological resemblance. In the interaction of HDL withT. brucei, HDL is named trypanolytic factor (TLF), because endocytosis of certain HDL subspecies, which contain haptoglobin-related protein (Hpr, TLF-1 [98]) and apolipoprotein L-I (Apo L-I, TLF-2 [99]), causes lysis ofT. b. bruceiand protects mammalian hosts from infection [100]. However,T. cruzihas developed resistance to TLFs. The exact mechanism of this resistance is currently unknown.The interaction between HDL andT. cruziwas recently reinforced by the discovery that the major structural component of HDL, apolipoprotein A-I (Apo A-I, full-length 28.1 kDa), is truncated into fragments (24.7, 13.6, 10.3, and 9.3 kDa) in sera ofT. cruziinfected patients [101]. Apo A-I (243 amino acids) accounts for ~75% of HDL protein content [102]. Both the N- and the C-termini of Apo A-I are involved in lipid binding functions [103–105]. The central domain of the Apo A-I protein is involved in the activation of lecithin-cholesterol acyltransferase (LCAT), which is responsible for the esterification and storage of cholesterol within HDL particles [106]. Minor changes in the Apo A-I amino acid sequence or structure could seriously affect HDL function [107]. Therefore, Apo A-I truncation seen inT. cruziinfection may contribute to the dysregulation of host lipid metabolism. The effect of this dysregulation needs to be further investigated. However, the unique truncation pattern seen in these patients has high discriminatory power between infected and uninfected patients and can be used asT. cruzidiagnostic biomarkers [101, 108, 109].Our research has revealed that the series of Apo A-I truncations was facilitated by the major cysteine protease ofT. cruzi, cruzipain [56], which is also known as GP 57/51 or cruzain. This protease which belongs to the mammalian papain superfamily is known to cleave immunoglobulin class G proteins [110, 111]. Cruzipain has an essential function in the invasion and survival processes ofT. cruziand is expressed in all developmental stages of the parasite life cycle [110]. At each stage, cruzipain is differentially located within the parasite to carry out stage specific functions [112, 113]. In theT. cruzitrypomastigote form, cruzipain is located on the parasite surface, flagellar pocket, and lysosome-like structure [114, 115].It was also shown that cruzipain was only able to cleave Apo A-I at an acidic pH, which suggests that the cleavage may take place within acidic environments. Furthermore, cruzipain from parasite surface (Figure2(a)) and cruzipain within the lysosome-like structure (Figure 2(b)) are both required in order to produce the truncation pattern [56]. It is interesting to note that the localization of cruzipain highly resembles that oftrans-sialidase. Therefore, it is possible that HDL is both endocytosed by trypomastigotes and bound to the surface of the parasite viatrans-sialidase. During the infection process, the parasite bound HDL is cleaved by cruzipain in the acidic parasitophorous vacuole.Possible mechanisms ofT. cruzicruzipain cleaving Apo A-I in HDL.T. cruzicruzipain is expressed in the parasitic surface as well as in the lysosomal-like structure/reservosome. Both cruzipain fractions are required to produce the full Apo A-I truncation profile seen inT. cruziinfected human patients. This implies that Apo A-I within the HDL complex may be (a) truncated during the infection process on the parasitic surface and also (b) endocytosed byT. cruzi and processed in the reservosome for possible lipid utilization.
(a)
(b)With the emerging evidence, it is becoming obvious thatT. cruziexploits the complex cholesterol transport system via a variety of molecules such as LDL, LDL-R, and HDL. The results of these interactions seem to all lead to the establishment ofT. cruziinfection and Chagas disease chronicity. The impact of these relationships on host lipid metabolism is yet to be investigated.


## 5. Conclusion

Host lipid metabolism is a intricate system involving a wide range of factors. It interacts with other energy metabolic systems as well as the immune system. The role of host lipid metabolism in response to infectious agents is drawing increasing attention. This review may aid in deeper understanding ofT. cruziinteracting with host lipid metabolism with a more systematic approach, as well as the role of lipids inT. cruzipathogenesis. We have clearly illustrated thatT. cruziinteracts with several specific factors in host lipid metabolism. Further research in these interactions and the role of lipids inT. cruzipathogenesis will be highly useful in the future.



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