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Enzymatic Complexes in Trypanosoma cruzi Surface: Implications for Host-parasite Interaction

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Guilherme C. Lechuga and Salvatore G. De-Simone

Submitted: 16 May 2023 Reviewed: 22 September 2023 Published: 04 October 2024

DOI: 10.5772/intechopen.113268

Trypanosoma - Recent Advances and New Perspectives IntechOpen
Trypanosoma - Recent Advances and New Perspectives Edited by Saeed El-Ashram

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Trypanosoma - Recent Advances and New Perspectives [Working Title]

Dr. Saeed El-Ashram, Dr. Abdulaziz Alouffi and Prof. Dkhil Mohamed

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Abstract

Chagas disease, a neglected tropical disease that affects millions of people worldwide, is caused by Trypanosoma cruzi. The surface of this flagellated parasite is coated with a dense layer of glycoproteins, which play key roles in host-parasite interactions. Among these proteins, enzymatic complexes have been identified, which are involved in several biological processes such as host cell invasion, immune evasion, and nutrient uptake. In this chapter, we review the current knowledge on the enzymatic complexes present in T. cruzi surface, including their structures, functions, and interactions with host molecules. We also discuss the potential of these complexes as targets for the development of novel therapies against Chagas disease. Overall, this chapter provides a comprehensive overview of the enzymatic complexes in T. cruzi surface, highlighting their importance in the pathogenesis of Chagas disease and their potential as therapeutic targets.

Keywords

  • Trypanosoma cruzi
  • Chagas disease
  • enzymes
  • membrane
  • surface proteins

1. Introduction

Chagas disease, also known as American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi. Approximately 6–7 million people are infected with T. cruzi in Latin America, with 75 million at risk of infection. The disease is endemic in 21 Latin American countries, and its global burden is estimated to be around 7.000 deaths annually [1, 2]. In some endemic areas, Chagas disease is mainly responsible for heart failure and is potentially fatal [3]. Chagas disease spreads to non-endemic areas due to migratory flux and the transmission by blood transfusion and organ transplants [4]. Vectorial transmission was significantly reduced but still occurs, oral transmission has also been a public health concern [5]. It is a silent disease, usually asymptomatic in the acute phase, is difficult to diagnose, and often progresses to the chronic phase. Infected individuals may remain asymptomatic (indeterminate form) for a long period or develop symptoms that include cardiac, gastrointestinal (megacolon and megaesophagus), neurological, or cardio-digestive manifestations [6].

T. cruzi has a complex life cycle, involving several developmental stages, and can infect a wide range of host species. This parasite has a remarkable degree of genetic variability, presenting multiple strains, classified into seven Discrete Typing Units (TcI-TcVI) and TcBat [7]. T. cruzi has three classical developmental forms, trypomastigotes and amastigotes, infecting mammals, and epimastigotes the replicative form in T. cruzi vector gut [8]. Infected vectors, hematophagous insects of the Reduviidae family, release metacyclic trypomastigotes in excreta, that penetrate the vertebrate host, through the bite, conjunctiva, or small lesions in the skin. Trypomastigotes invade cells in the vertebrate host, mainly muscle cells, fibroblasts, and macrophages [9]. Several proteins in T. cruzi surface mediate the attachment and penetration of the parasite in the host cell firing several signaling cascades that lead to Ca+2 intracellular increase, lysosome migration, and parasitophorous vacuole (PV) formation [10, 11]. T. cruzi escapes from PV and differentiates into round amastigote form that replicates in the host cell cytoplasm, subsequently it differentiates from trypomastigotes that are released after host cell rupture [9]. The parasite has evolved various mechanisms to adapt to different hosts and evade the host immune response, including the expression of enzymatic complexes on its surface, such as the trans-sialidase (TS), Gp63 metalloproteases, and GSC complex [12].

Protein complexes are essential for the survival and virulence of the parasite, as they play crucial roles in the modulation of host cell signaling, the induction of cytokine release, and the evasion of the host immune response [12]. As a parasite, T. cruzi needs to invade and replicate in host cells. There are several ways that T. cruzi invades the host cell, such as engaging host cell surface receptors, shedding molecules, and creating mechanical damage to the host cell plasma membrane [13, 14, 15, 16]. These mechanisms lead to events in host cells for parasite invasion like Ca2+dependent recruitment of lysosomes, endocytosis, and autophagy [11], and subsequently the formation of the TcPV where T. cruzi is localized. T. cruzi also manipulates host cell signaling pathways to avoid apoptosis, which is essential for establishing a productive infection [13, 17]. During the invasion, signaling pathways cascades are activated in both the parasite and host cell [18]. Recently, the importance of shedding extracellular vesicles was highlighted for parasite invasion, communication, and parasite-host interaction [19, 20]. In all these events, the involvement of membrane proteins and enzymes is crucial.

Due to the high morbidity and burden associated with Chagas disease, and the lack of effective therapies, there is a pressing need to develop new treatments that target T. cruzi unique surface architecture. Current drugs (Benznidazole and Nifurtimox) have many side effects, are ineffective in the chronic phase, and some strains are naturally resistant [21]. Understanding the structure and function of enzymatic complexes such as the Trans-sialidase (TS) family, Gp63 metalloprotease, and Gamma-secretase complex (GSC) is essential for the design of effective therapies for Chagas disease. In this chapter, we will discuss recent data on enzymatic complexes in parasite surface and host-cell interplay.

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2. Composition and structure of the T. cruzi surface coat

The surface coat of T. cruzi is composed of a complex array of molecules, including glycoproteins, lipids, and carbohydrates. Among these, enzymatic complexes play a critical role in the pathogenesis of Chagas disease by modulating host-parasite interactions. The enzymatic complexes present in the T. cruzi surface coat are diverse and include trans-sialidases, Gp63 metalloproteases, as well as other complexes such as the gamma-secretase complex. The surface coat of T. cruzi is composed of a lipid bilayer and the associated components that interact with the extracellular space and form the surface coat or glycocalyx. Ultrastructure analysis revealed that T. cruzi has an array of sub-pellicular microtubules distributed in the parasite body, but not in the flagellar pocket region, the main site of exocytosis and endocytosis [22, 23, 24]. There is a large diversity of stage-specific molecules in T. cruzi surface with high polymorphism [25]. Molecules found on the cell surface of T. cruzi include the mucins, trans-sialidase family, Gp85 family, Gp63, Gp35/50, Cruzipain, Ssp-3, and TSSA, among others [25]. Trypomastigote membrane is highly organized and made up of multiple nanodomains with different protein compositions [26]. One of the main types of parasite surface molecules is the GIPLs and O-glycosylated mucins, which are glycoproteins bound to the plasma membrane through a GPI anchor [27]. These molecules are abundant and play a significant role in the interaction between T. cruzi and host cells. There are also several other families of molecules that are involved in T. cruzi’s adhesion to and invasion of host cells. The removal of surface proteins from trypomastigotes through proteolytic treatment significantly reduced parasite invasion, indicating a link between these proteins and infectivity [28]. The study of proteins and carbohydrates in T. cruzi surface progresses and parasite stage-specific glycoprotein, as well as interactions with host cell receptors and signaling cascade, are currently known [26, 27, 29, 30, 31]. Mass spectrometry was applied to study T. cruzi’s glycoproteome, which identified 690 glycoproteins. A subset of these glycoproteins was found exclusively in epimastigotes and trypomastigotes [32].

Most of these surface glycoproteins have a cellular receptor to engage an intracellular cascade that contributes to parasite attachment, invasion, or immune evasion. In metacyclic trypomastigotes, Gp82 is involved in the invasion. It is a member of the gp85/TS family anchored to the outer cell membrane of the parasite by a GPI anchor, which can be cleaved by a phosphatidylinositol-specific phospholipase C. During the invasion process, the gp82 molecules that are secreted or still attached to the surface of the parasite interact with a receptor on the host cell. This interaction triggers signaling pathways that mobilize intracellular Ca2+ and lysosomes of the host cell to the invasion site [18, 33, 34]. Likewise, Gp35/50 binds to a host cell and triggers an increase in intracellular Ca2+ levels [35]. However, gp35/50-mediated invasion causes the recruitment of actin, while gp82 causes the disassembly of actin filaments by triggering specific signaling pathways [36]. Some of the proteins in T. cruzi surface are enzymes, organized in complexes, that have crucial activity in parasite invasion and survival (Figure 1). In the next section of the chapter, we will discuss the available data on the T. cruzi surface enzymatic complexes.

Figure 1.

T. cruzi surface coat enzyme complexes. These membrane proteins are attached to the parasite surface by transmembrane domains or glycosylphosphatidylinositol (GPI) anchors, they are responsible for parasite adhesion, invasion, protection, immune evasion, secretory and endocytic pathways, and parasite metabolism. Among the most relevant enzymes are the cysteine protease (Cruzipain), metallopeptidase (Gp63), aspartyl peptidases (Gamma-secretase complex: Presenilin and Nicastrin), Trans-sialidases, and Phospholipase A1.

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3. Enzymatic complexes present in the T. cruzi surface coat

3.1 Trans-sialidases

One of the molecules involved in the invasion of trypomastigotes is trans-sialidase (TS), which is a critical virulence factor for the parasite. Since the parasite cannot produce sialic acid (SA), TS enables the parasite to transfer SA residues from the host cell donor to mucins on the parasite membrane [37]. This process generates a sialylated surface that helps the parasite evade the immune system, promoting its survival and the establishment of the disease [38, 39]. TS also plays a role in promoting the invasion of the host cell by creating the Stage-Specific Epitope 3 (Ssp-3) [40]. The signaling pathways implicated in TS-mediated invasion include the PI3K/AKT and MAPK/ERK (mitogen-activated protein kinase/extracellular-regulated kinase) pathways [41, 42]. Shedding of TS into the bloodstream allows T. cruzi to manipulate the surface sialylation pattern of the target cell and other cell types distant from the site of infection, which can lead to immunomodulation and hematological alterations [43]. There is differential TS expression between different T. cruzi strains, with highly virulent strains expressing and shedding more TS than low-virulence strains [44, 45].

Trans-sialidases (TS) are found throughout the parasite body, including on the parasite’s flagellum and the flagellar pocket [46]. The TS superfamily is categorized into four groups based on the molecules’ sequence identity and functional properties [47].

Group I comprises proteins with trans-sialidase activity, which transfers sialic acid from host cell glycoconjugates to trypomastigote mucins, and/or neuraminidase activity, which releases sialic acid into the milieu. Sialylation is essential for the survival and propagation of T. cruzi in host cells and immune evasion [48], and neuraminidase activity is a crucial element for parasite internalization [49]. The members of TS Group I in the bloodstream trypomastigote stage are T. cruzineuraminidase (TcNA) and shed acute-phase antigen (SAPA), while epimastigote trans-sialidase (TS-epi) is the Group I TS in the epimastigote stage. Shade acute phase antigen (SAPA) and Neuraminidase (TcNA) are anchored to the parasite’s plasma membrane by a glycosylphosphatidylinositol (GPI), whereas TS-epi has a transmembrane domain (Figure 2) [25, 51].

Figure 2.

General representation of trans-sialidase activity in T. cruzi. TS enables the parasite to transfer sialic acid (SA) residues from the host cell donor to mucins on the parasite membrane, this process generates a sialylated surface important for parasite virulence, survival, and immune evasion. TS is anchored by a glycosylphosphatidylinositol (GPI) in trypomastigotes, the tridimensional structure of trans-sialidase (PDB: 1ms3, blue) was attached to GPI anchor (orange) in C-terminal and orientation was evidenced in membrane model (gray) using CHARMM-GUI membrane builder [50].

The second group of T. cruzi TS consists of various members of the Gp85 surface glycoprotein family, including Amastigote surface proteins (ASP-1 and ASP-2), trypomastigote surface antigen (TSA-1), Tc85, SA85, GP82, and GP90. They are all associated with the binding and invasion of host cells [52, 53]. These proteins are anchored to the parasite membrane by GPI [25]. ASP-1 and ASP-2 are amastigote surface proteins, whereas TSA-1 is a trypomastigote surface antigen, these proteins were found to be highly immunogenic [54, 55]. The glycoprotein Tc85 is expressed in bloodstream trypomastigotes, it binds extracellular matrix (fibronectin and laminin) and host receptor molecules located on the cell surface [56]. Gp82 and Gp90 are expressed on the metacyclic trypomastigote surface and have been shown to activate parasite internalization and regulate parasite invasion, respectively [35, 57].

The third group of T. cruzi is made up of surface proteins found in bloodstream trypomastigotes, including complement regulatory protein (CRP), FL160, chronic exoantigen (CEA), and trypomastigote excretory-secretory antigens (TESA), which can inhibit complement activation pathways to protect the parasite against host lysis [25, 39]. The fourth group consists of genes encoding trypomastigote surface antigens whose biological function remains unknown, with Tc13 being a representative protein [25].

3.2 Gp63 metalloproteases

Trypanosomes and Leishmania species have a family of zinc-dependent metalloproteases, major surface protease (MSP), expressed on their cell surface, which is also known as Gp63 or leishmanolysins. T. cruzi has Gp63-like genes (TcGP63) that are differentially regulated, indicating their functional importance at various stages in the parasite’s life cycle [58]. The TcGp63 family can be divided into two groups of proteins, TcGP63-I and TcGp63-II. The TcGP63-I was found in all three life stages of T. cruzi. These proteins exhibit metallopeptidase activity and are implicated in the degradation of extracellular matrix and cytosolic proteins including intracellular peptides presented by major histocompatibility complex class I (MHC-I) molecules, resistance to antimicrobial peptides, and cleavage of complement components [59]. TcGp63 is attached to the parasite’s membrane by a GPI anchor and has two isoforms, glycosylated and non-glycosylated, found in similar levels in both epimastigote and amastigote forms [58]. The non-glycosylated isoform is located intracellularly near the kinetoplast and the flagellar pocket of the metacyclic trypomastigote [58]. TcGp63 plays an important role in the interaction of T. cruzi with the insect vector, parasites isolated after insect colonization had elevated expression of Tcgp63-I and anti-TcGp63-I antibodies decreased T. cruzi adhesion to Rhodnius prolixus midgut [60]. AntiGp63-specific antisera partially block the in vitro invasion of mammalian cells by trypomastigotes [61].

3.3 TcPLA1

The phospholipase A1 (TcPLA1) is a protein associated with the membrane and secreted that can be found in the extracellular medium of tissue-derived trypomastigotes and extracellular amastigotes (EAs) [62, 63]. The conditioned medium with extracellular vesicles and exosomes of EAs, trypomastigotes, or recombinant TcPLA1 can modify the lipid profiles of host cells, leading to increased concentrations of free fatty acids, diacylglycerol, and lysophosphatidylcholine [62, 63]. TcPLA1 leads to the activation of PKC pathway, which has been linked to parasite invasion, suggesting that Tc-PLA1 is involved in the events preceding host cell invasion [64].

3.4 Cruzipain

Cruzipain (Czp) is the most expressed cysteine peptidase in T. cruzi, there are several isoforms in all forms of T. cruzi, and is primarily located in lysosome-related organelles, but it is also secreted or remains membrane-bound [65, 66]. Trypomastigotes can secrete this cysteine proteinase to the extracellular medium [67, 68]. Czp, a papain-like proteinase, has an important role in the invasion [69]. When released by trypomastigote, Czp facilitates invasion by producing bradykinin from kininogen on the host cell surface through its cysteine protease activity. Subsequently, triggers IP3-mediated Ca2+ signaling upon binding to the bradykinin B2 receptor (B2R) [70]. A second cruzipain-mediated route was discovered for trypomastigotes, that is not blocked by kinin receptor antagonists, but was blocked by thapsigargin, a cysteine protease inhibitor. Experimental evidence suggests that this effect is due to a soluble trypomastigote-associated factor or parasite-shed membranes released by Czp [68]. Cruzipain is most active in epimastigotes, expression of cruzipain is important for parasite adhesion in the midgut of Rhodnius prolixus [71]. The enzyme’s subcellular location varies throughout the parasite’s biological cycle. During the epimastigote stage, cruzipain is primarily present in the reservosome, a specific organelle from epimastigotes that stores and digests protein during differentiation into metacyclic trypomastigotes [72]. The inhibition of cruzipain activity prevents metacyclogenesis [73]. Czp also has an importance in immune evasion, T. cruzi can block the Fc-dependent effector functions of specific antibody using cruzipain activity by hydrolyzing the Fc of human IgG, impairing its binding to FcR [74]. Taken in consideration the importance of Czp for the survival of the parasite, this enzyme has been extensively studied and validated as a chemotherapeutic target [75, 76, 77, 78]. Cruzipain inhibitors in pre-clinical studies have been tested with high efficacy, not only inhibiting growth but killing the parasite [79]. N-Methylpiperazine-Phe-homoPhe-vinyl sulphone phenyl (K777), a lead compound had in vivo efficacy after treatment of T. cruzi-infected mice leading to undetectable parasite load [79] with comparable effect in an immunodeficient mouse model [80].

3.5 Gamma-secretase complex

Gamma-secretase complex is involved in the maturation and processing of type 1 proteins destined for cell membranes, it is composed of aspartic peptidase presenilin (PS), anterior pharynx-defective 1 (Aph1) protein, Nicastrin, and presenilin enhancer 2 (PEN-2) [81]. Gamma-secretase complex is involved in the processing of the amyloid precursor protein (APP), releasing the amyloid beta peptide, loss of function of PS is related to the development of Alzheimer’s disease [82]. The first speculations of the presence of analogous proteins in T. cruzi were reported when aspartic peptidase activity was found in parasite membrane-enriched extracts [83]. Recently, T. cruzi presenilin-like transmembrane protein was reported, and bioinformatics showed that it contains nine transmembrane domains and an active site with the conserved PALP motif of the A22 family. Using polyclonal antisera revealed a cyto-localization in all parasite forms, the signal was primarily localized to the flagellar pocket, intracellular vesicles, and endoplasmic reticulum by immunofluorescence. These results suggest a role of the presenilin-like enzyme in the secretory pathway [84]. Nicastrin-like protein was also reported, TcNICT has a large extracellular domain with numerous glycosylation sites and a single-core transmembrane domain important for the γ-secretase complex stabilization. Confocal microscopy suggests that TcNICT is localized in the flagellar pocket and membrane nanodomains. The anti-Tc/NICT polyclonal serum partially blocked parasite entry in Vero cells [85], but further studies are needed to establish if GSC serves as a target for the generation of new therapeutics for T. cruzi (Figure 3).

Figure 3.

3D structure of T. cruzi Gamma-secretase complex proposed by Lechuga and co-workers [84, 85]. Model of T. cruzi PS (TcPS; pink) showed 9 transmembrane domains with a huge intracellular loop between TM6 and TM7 containing sites for endoproteolytic cleavage. TcPS have the highly conserved domain in the PS-like catalytic pocket (YD and GLGD). The other described component of GSC is Nicastrin (TcNICT; blue), with one TM domain and a large extracellular area important for GSC stabilization.

Aspartic peptidases have been studied as a potential target for T. cruzi. Pepstatin A, an inhibitor of GSC and aspartic peptidases significantly arrested parasite proliferation [86]. Also, HIV aspartic peptidase inhibitors impaired trypomastigote viability and altered parasite morphology [87]. Additionally, nelfinavir and lopinavir significantly reduced number of intracellular amastigotes in vitro [88].

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4. Conclusions

Chagas disease, caused by the protozoan parasite T. cruzi, remains a significant public health concern in Latin America and poses a growing threat in non-endemic areas. The parasite surface coat, composed of a diverse array of molecules including glycoproteins, lipids, and carbohydrates, plays a critical role in host-parasite interactions and pathogenesis. Enzymatic complexes present in the T. cruzi surface coat have been found to be essential for the parasite’s survival, virulence, and modulation of host cell signaling. Current treatments have limitations, including side effects, ineffectiveness in the chronic phase, and natural resistance of some parasite strains. Targeting the unique surface architecture of T. cruzi, particularly the enzymatic complexes involved in host-parasite interactions, holds promise for the design of novel therapeutic strategies. Advances in bioinformatics, mass spectrometry, and proteomic techniques have provided valuable insights into the glycoproteins and carbohydrate structures present on the T. cruzi surface. The identification of stage-specific molecules, their interactions with host cell receptors, and their roles in signaling cascades are areas of active investigation. In conclusion, a comprehensive understanding of the enzymatic complexes present in the T. cruzi surface coat is crucial for the development of targeted interventions against Chagas disease. The ongoing research in this field offers promising avenues for the design of novel therapeutic approaches that can effectively target the parasite.

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Conflict of interest

The authors declare no conflict of interest.

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Written By

Guilherme C. Lechuga and Salvatore G. De-Simone

Submitted: 16 May 2023 Reviewed: 22 September 2023 Published: 04 October 2024

© 2023 The Author(s). Licensee IntechOpen. This content is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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