Abstract
Trypanosoma cruzi (T. cruzi) is a protozoan parasite that causes Chagas disease, a zoonotic disease that can be transmitted to humans by blood-sucking triatomine bugs. T. cruzi is a single-celled eukaryote with a complex life cycle alternating between reduviid bug invertebrate vectors and vertebrate hosts. This article will look at the developmental stages of T. cruzi in the invertebrate vector and the vertebrate hosts, the different surface membrane proteins involved in different life cycle stages of T. cruzi, roles of different amino acids in the life cycle, carbon and energy sources and gene expression in the life cycle of T. cruzi. The author will also look at extracellular vesicles (EV) and its role in the dissemination and survival of T. cruzi in mammalian host.
Keywords
- Trypanosoma cruzi
- metacyclogenesis
- trypanosomatid
- epimastigote
- metacyclic trypomastigotes
- extracellular vesicles
1. Introduction
The genus
2. The life cycle of Trypanosoma cruzi
The life cycle of
The general view of the life cycle of
Metacyclic parasite forms express a set of surface glycoproteins that interact with mammalian cells [13, 14]. One of the glycoproteins, a metacyclic-stage-specific 82-kDa glycoprotein (gp82), has been implicated in host cell invasion [15]. The gp82 glycoprotein is an adhesion molecule that binds to host cells in a receptor-mediated manner and triggers Ca2+ mobilization [16] which is essential for parasite penetration [17, 18, 19, 20]. The gp82 also induces the activation of metacyclic trypomastigote protein tyrosine kinase [21] and an increase in the parasite intracellular Ca2+ concentration [22]. Other glycoproteins which are expressed in bloodstream or tissue-culture derived trypomastigotes and which are implicated in mammalian cell adhesion/invasion are gp83 [23], gp85 [24], and Tc-85 [25]. The gp83 has been reported to signal through the mitogen-activated protein kinase pathway to up regulate
3. Metacyclogenesis
Metacyclogenesis is the fundamental step in the life cycle of
Description of metacyclogenesis can be in two parts, the first leading to the second. Firstly, the trypanosome senses loss of sugars from its environment and responds by elongating its cell body and flagellum and by activating its mitochondrion which leads to the lengthening of the trypanosome flagellar membrane that is rich in sterol and more hydrophobic than the somatic membrane. Secondly, the lengthening of the flagellar permits the trypanosomes to adhere to a hydrophobic surface and it is this interaction that triggers metacyclogenesis. This trigger for metacyclogenesis is cyclic adenosine monophosphate (cAMP) mediated.
Cyclic AMP plays an important role in the control of lower eukaryotes differentiation [30, 31, 32]. The relative amounts of cyclic AMP can change according to the surrounding environment, enabling the organisms to adapt quickly to new conditions. The differential balance of cAMP may result in activation of protein kinases [33, 34], transcription of specific genes [35, 36, 37] and changes in the cytoskeleton structure [38], which ultimately lead to morphogenetic cell alterations. Cyclic AMP balance could vary as a response to a changing environment leading to differential gene expression and morphological changes allowing the parasite to go through its life cycle. Calmodulin is known to play a direct role in controlling the levels of cAMP in eukaryotic cells [39] and in the case of
4. The developmental stages of T. cruzi in vertebrate and invertebrate
The
5. Surface membrane proteins
Membrane proteins play an important role in the biology of
5.1 The mucins family
The second mucin protein family TcSMUG family is divided into two groups: TcSMUG S (small) and TcSMUG L (large) according to their encoded mRNA size [58, 62] and encodes for very small open reading frame containing a putative signal peptide at the N-terminus and a GPI-anchor signal in the C-terminus. The TcSMUG S group is found in the epimastigote and metacyclic trypomastigote forms and encodes for 35–50 kDa mucins N-glycosylated (Gp35/50 mucins) and they are the major acceptors of sialic acid on the parasite surface by parasite trans-sialidases in
5.2 The trans-sialidases (TS) protein family
The trans-sialidases (TS) protein family of
The TS I comprises of proteins with trans-sialidase (TS) and/or neuraminidase activities [74]. Neuraminidase activity occurs when nonsuitable acceptor molecules for sialic acid are present and then sialic acid is transferred to water [75]. Neuraminidase activity is involved in the removal of sialic acid from parasites and/or host-cell molecules which is required for parasite internalization [76]. The TS I members incudes: TCNA (neuraminidase), SAPA (shed acute-phase antigen), and TS-epi. SAPA and TCNA proteins are closely related with 84% homology at the amino acid level and have active trans-sialidase and neuraminidase activities and are expressed during bloodstream trypomastigote stage [77]. SAPA and TCNA have two main regions: an N-terminal catalytic region and a C terminal extension, which repeats 12 amino acids (SAPA repeats) in tandem with the consensus sequence. SAPA has only 14 tandem repeats compared to 44 for TCNA and the presence of SAPA repeats increases the half-life of the protein in the blood [78]. Both proteins are attached by glycosylphosphatidylinositol to the parasite plasma membrane and can be found in the serum of deeply infected mammals.
TS-epi, the third member of group TS I is an active trans-sialidase expressed in the insect dwelling epimastigote form at the stationary phase and is different from the trans-sialidase expressed of the blood trypomastigotes. Unlike other members of the group, TS-epi lacks SAPA repeats and is not attached to the membrane by glycosylphosphatidylinositol.
Members of TS group II includes: ASP-1, ASP-2, TSA-1, Tc85, SA85, GP82, and GP90 and they all have been implicated in host-cell attachment and invasion. ASP-1, ASP-2 (both are amastigote surface proteins) and TSA-1 (trypomastigote surface antigen) are targets of
TS Group III which is formed by surface proteins present in mammal bloodstream trypomastigotes includes: complement regulatory protein (CRP), surface flagellar protein (FL-160), chronic exoantigen (CEA), and trypomastigote excretory-secretory antigens (TESA) [79]. These surface proteins are recognized by sera from patients infected with Chagas’ disease and they are able to inhibit the classical and the alternative pathways of complement activation, which could be a protection from lysis by the host in the trypomastigote form [80, 81]. TESA is distributed on the cell surface membrane of
The TS Group IV is included in the trans-sialidase superfamily because it contains the conserved motif VTVxNVxLYNR, which is shared by all known TS members and is composed of genes encoding trypomastigote surface antigens whose biological function is still unknown [84, 85]. The TsTc13 protein, a member of TS Group IV has been shown to be highly antigenic and is present in the infective metacyclic trypomastigote form [86].
5.3 TcGP63 family
This protein is expressed by trypanosomes and
5.4 Amastin family
The amastin family which is a group of transmembrane glycoproteins consists of small proteins of about 180 amino acids. The genome of
5.5 T . cruzi trypomastigote alanine, serine and valine (TcTASV) family
The TcTASV protein family is conserved among all the
5.6 Mucin-associated surface proteins (MASPs) family
The MASP family is characterized by having highly conserved N and C-terminal domains and a variable and repetitive central region, with a maximum expression in the human infective stages of the parasite. MASP are expressed simultaneously in bloodstream trypomastigotes as well as in amastigotes and epimastigotes and MASP molecules are the most abundant antigens found on the surface of the infective trypomastigote stage of
5.7 Cruzipain family
This glycoprotein is synthesized as a zymogen that is activated by cleavage of the N-terminal pro-domain to generate the mature protease and belongs to the mammalian papain superfamily but contains, as other cysteine proteases (CPs) from trypanosomatids, an unusual C-terminal extension. Cruzipain family has many groups which include: native-cruzipain (N-cruzipain), recombinant-cruzipain 1 (R-cruzipain 1) and recombinant cruzipain 2 (R-cruzipain 2). Cruzipains are expressed on all the body surface of epimastigotes and amastigotes forms while in the trypomastigote form, cruzipain is expressed only in the flagellar pocket region. Cruzipain plays a role in the process of
6. Extracellular vesicles in the life cycle of T. cruzi
Extracellular vesicles (EVs) typically consist of a lipid bilayer membrane containing integral membrane proteins and a luminal cavity that is loaded with a variety of soluble proteins and nucleic acids.
Immune cells are one of the main targets of extracellular vesicles. Extracellular vesicles secreted during acute and/or chronic
7. Carbon and energy sources in T. cruzi life cycle
The life cycle of
Trypanosomatids can use either glucose or amino acids as main carbon and energy source, although one cannot rule out the use of fatty acids as well. Amino acids, especially l-proline and l-glutamine which are abundant in the hemolymph and tissue fluids of the blood sucking vector are the main source of carbon and energy in the insect stages. l-Proline seems to be involved in several mechanisms of resistance to oxidative, nutritional and thermal stress and is important in metacyclogenesis for the differentiation of intracellular epimastigotes to trypomastigotes in
Amino acids are crucial nutrients during the
8. Changes in gene expression during the life cycle of T. cruzi
As a result of changing environments during the life cycle,
Cellular differentiation is controlled at multiple levels including, for most eukaryotic cells, initiation of gene transcription. The discriminatory mechanisms for the initiation of transcription at individual loci is largely absent in trypanosomatids and most protein-coding genes lack promoters and are transcribed as long polycistronic units that are processed into individual mRNAs. Consequently, trypanosomes rely on post-transcriptional processes such as translational efficiency, mRNA stability and post-translational modification to coordinate developmental transitions and other adaptive responses encountered throughout their complex life cycles.
In eukaryotes, protein-coding genes are transcribed into monocistronic pre-mRNA transcripts containing coding sequences (exons) and non-coding sequences (introns) that are processed into mature mRNAs through
Granules of mRNA such as processing bodies (P bodies) and stress granules (SGs) are involved in post-transcriptional regulation of gene expression. P bodies are constitutively present in the cell and can grow in size and number when cells are perturbed while SGs only arise under cellular stress. P bodies contain mRNA and proteins involved in translational repression, mRNA decapping, 5′ → 3′ mRNA decay, nonsense-mediated decay (NMD) and the miRNA (microRNA) pathway. P bodies were initially thought to be the place where mRNA was recruited to be degraded and recently, a function as mRNA storage depots has been assigned to P bodies. By contrast, SGs are stalled 43S translation pre-initiation complexes, mainly composed of mRNA, translation initiation factors and 40S ribosomal proteins. SGs are thought to function as mRNA triage centers during stress.
9. Conclusion
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