Memórias do Instituto Oswaldo Cruz Fundação Oswaldo Cruz, Fiocruz ISSN: 1678-8060 EISSN: 1678-8060 Vol. 104, Num. s1, 2009, pp. 76-88

Memórias do Instituto Oswaldo Cruz, Vol. 104, No. supp 1, July, 2009, pp. 76-88

A century of research: what have we learned about the interaction of Trypanosoma cruzi with host cells?

Maria Julia Manso Alves^I; Renato Arruda Mortara^{II, +}

^IDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil
^IIDisciplina de Parasitologia, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, Escola Paulista de Medicina, Rua Botucatu 862 6º andar, 04023-062 São Paulo, SP, Brasil
+ Corresponding author: ramortara@unifesp.br

Received 3 March 2009
Accepted 29 May 2009

Financial support: CNPq, CAPES, FAPESP, FINEP (MJMA)

Code Number: oc09095

ABSTRACT

Since the discovery of Trypanosoma cruzi and the brilliant description of the then-referred to "new tripanosomiasis" by Carlos Chagas 100 years ago, a great deal of scientific effort and curiosity has been devoted to understanding how this parasite invades and colonises mammalian host cells. This is a key step in the survival of the parasite within the vertebrate host, and although much has been learned over this century, differences in strains or isolates used by different laboratories may have led to conclusions that are not as universal as originally interpreted. Molecular genotyping of the CL-Brener clone confirmed a genetic heterogeneity in the parasite that had been detected previously by other techniques, including zymodeme or schizodeme (kDNA) analysis. T. cruzi can be grouped into at least two major phylogenetic lineages: T. cruzi I, mostly associated with the sylvatic cycle and T. cruzi II, linked to human disease; however, a third lineage, T. cruziIII, has also been proposed. Hybrid isolates, such as the CL-Brener clone, which was chosen for sequencing the genome of the parasite (Elias et al. 2005, El Sayed et al. 2005a), have also been identified. The parasite must be able to invade cells in the mammalian host, and many studies have implicated the flagellated trypomastigotes as the main actor in this process. Several surface components of parasites and some of the host cell receptors with which they interact have been described. Herein, we have attempted to identify milestones in the history of understanding T. cruzi- host cell interactions. Different infective forms of T. cruzi have displayed unexpected requirements for the parasite to attach to the host cell, enter it, and translocate between the parasitophorous vacuole to its final cytoplasmic destination. It is noteworthy that some of the mechanisms originally proposed to be broad in function turned out not to be universal, and multiple interactions involving different repertoires of molecules seem to act in concert to give rise to a rather complex interplay of signalling cascades involving both parasite and cellular components.

Key words: Trypanosoma cruzi - cellular invasion - trypomastigotes - amastigotes - parasitophorous vacuole escape - phylogenetic lineages

Outlook

Since the pioneering studies by Hertha Meyer and co-workers (Meyer 1942, Meyer & Xavier 1948), which initiated in vitro studies of Trypanosoma cruzi development in cultured cells, and the subsequent detailed descriptions provided by James Dvorak and co-workers on how cells become infected by T. cruzi trypomastigotes (Dvorak & Hyde 1973, Dvorak & Howe 1976), numerous studies have been undertaken to elucidate the molecular mechanisms that underlie the complex process of parasite entry into mammalian host cells. In order to accomplish these studies, a great deal of effort has been devoted to isolating parasites and determining the optimal conditions for their growth and differentiation (Camargo 1964, Baker & Price 1973, Pan 1978a, Engel et al. 1982, Villalta & Kierszenbaum 1982, Petry et al. 1987, De Souza 2000). A number of significant contributions have provided insights into both the ultrastructural organisation of the parasite (De Souza 2008) and the participation of both parasite and cellular in infection (Zingales & Colli 1985, De Souza 2000, Alves & Colli 2008). In Fig. 1, we have selected milestones that help to describe a trajectory of discovery that, like that of science in general, is not linear in time. Because several events overlap in time and relevance and therefore cannot be dissociated, references to particular findings may appear more than once. It is noteworthy that some of these events were initially thought to be of general importance in the biology of T. cruzi-host cell interactions, yet later turned out to be restricted to a particular parasite strain, clone or even target host cell. It has become increasingly apparent that a complex interplay of signalling cascades, involving both parasitic and cellular components, seem to operate in the infection process (Burleigh & Andrews 1995b, 1998, Burleigh & Woolsey 2002, Yoshida 2006, Alves & Colli 2007, Scharfstein & Lima 2008, Yoshida & Cortez 2008). The parasite infective forms considered herein are metacyclic (MT) and tissue-culture derived trypomastigotes (TCTs), as well as extracellular amastigotes (Fig. 2); bloodstream trypomastigote forms have also been studied by several laboratories, and their in vitro and in vivo behaviour is more similar to that of TCTs than MTs (Brener 1969, Gutteridge et al. 1978, Kipnis et al. 1979, Krettli et al. 1979, Alcantara & Brener 1980, Meirelles et al. 1982b, Wirth & Kierszenbaum 1984, Zwirner et al. 1994, Gomes et al. 1995, Alves & Colli 2007). More recently, it was discovered that there are differences in the invasion mechanisms engaged by the distinct infective forms of the parasite from the two major phylogenetic lineages, an observation that has opened new avenues to study this already intricate process (Mortara et al. 2005, 2008, Yoshida 2006, 2008).

It is generally accepted that in order for cell invasion to occur, T. cruzi infective forms need to physically attach to the host cell surface. This process usually takes a few minutes in vitro, and it is not uncommon to observe trypomastigotes attaching and detaching from a target cell, as if 'probing' it before invasion (Dvorak & Hyde 1973, Dvorak & Howe 1976, Nogueira & Cohn 1976, Andrews & Colli 1982, Meirelles et al. 1982a, Lima & Villalta 1988, Schenkman et al. 1991c, Villalta et al. 1992b). Attachment can be separated from invasion by lowering the temperature or fixing target cells (Andrews & Colli 1982, Meirelles et al. 1982a, Schenkman et al. 1991c). Several lines of evidence suggest that motile trypomastigotes promptly attach to and invade live cells through an active mechanism that does not require intact host cell microfilaments (Kipnis et al. 1979, Schenkman et al. 1991c, Schenkman & Mortara 1992), but instead depends on parasite energy (Schenkman et al. 1991c). In contrast, extracellular amastigotes do not attach to fixed cells, and their invasion depends on functional host cell microfilaments (Mortara 1991, Procópio et al. 1998, Mortara et al. 2005). Once attachment is established, signals exchanged (see above references and section below) activate parasite-driven invasion of trypomastigotes (Kipnis et al. 1979, Schenkman et al. 1991c, Schenkman & Mortara 1992) or induce "phagocytosis-like" entry of amastigotes (Nogueira & Cohn 1976, Procópio et al. 1998, 1999).

It has been demonstrated that a number of parasite and host cell components (such as proteins/glycoproteins and other glycoconjugates) participate in the attachment phase of the invasion process (Burleigh & Andrews 1995b, 1998, Burleigh & Woolsey 2002, Andrade & Andrews 2005, Alves & Colli 2007, Yoshida & Cortez 2008) and consequently play a role in signalling exchanges. More recently, it has also been shown that lipid rafts in the host membrane may also take part in this process (Barrias et al. 2007, Fernandes et al. 2007a). The complexity of the invasion process can be gleaned from the examples provided in the section dealing with the multitude of signalling events involving T. cruzi- host cell interactions.

Another important factor of the multitude of studies in this area is the extensive variety of host or target cells. These include macrophages, epithelial and endothelial cells, fibroblasts, dendritic cells, neurites as well as cardiomyocytes (Meyer 1942, Meyer & Xavier de Oliveira 1948, Nogueira & Cohn 1976, Henriquez et al. 1981, Meirelles et al. 1982a, 1987, 1999, Morris et al. 1988, 1990, Schenkman et al. 1988, Araujo-Jorge 1989, Ortega-Barria & Pereira 1991, Aprigliano et al. 1993, Procópio et al. 1998, 1999, Huang et al. 1999, Chuenkova & Pereira 2001, Garzoni et al. 2003, Melo et al. 2004, Taniwaki et al. 2006, Coimbra et al. 2007, Bartholomeu et al. 2008, Lu et al. 2008, Poncini et al. 2008, Scharfstein & Lima 2008). This single variable exemplifies the multitude of host cell and parasite components that, upon interaction, lead to activation of the signalling pathways discussed below. Moreover, the plethora of molecules involved increases when different strains of parasite are compared. The analysis of the invasion mechanism (or mechanisms) of host cells by T. cruzi based on data from the literature can be restricted to one cell type-one or strain until more general conclusions can emerge. However, in the case of in vivo studies, the infection route must also be considered (Hoft 1996, Hoft et al. 1996, Yoshida 2008).

Biology of T. cruzi-host cell invasion

Paradigmatic studies have provided new insights into the invasion mechanisms of T. cruzi. Some of these studies have observed that calcium-dependent lysoso-mal recruitment takes place during trypomastigote invasion (Tardieux et al. 1992, Andrews 2002). According to this model, TCTs engage a signalling process that culminates with the formation of the parasitophorous vacuole (PV) (Burleigh & Andrews 1998, Burleigh & Woolsey 2002). Additional evidence suggests the participation of components of the early endocytic trafficking pathway, such as dynamin and Rab5, and indicates that the lysosomal process might be both more elaborate and downstream of earlier events (Wilkowsky et al. 2002). Previous studies (Todorov et al. 2000, Wilkowsky et al. 2001) have used a quantitative approach to identify the role of phosphatidyl-inositol 3-kinase (PI3-K) (Woolsey et al. 2003) in the lysosomal pathway and observed that this key cellular component is involved in a lysosome-independent T. cruzi internalisation pathway utilised by TCTs. Trypomastigotes that use this route mobilise phosphorylated inositides during the formation of the PV. These molecules then mature and become enriched in the same compartments as the lysosomal marker LAMP-1 (Tardieux et al. 1992, Procópio et al. 1998, Woolsey et al. 2003, Andrade & Andrews 2004, Fernandes et al. 2007b). One important outcome of this work was to demonstrate for the first time the relative contributions of each mode of entry, namely PI3-K (50%), lysosome (20%) and endosomal routes (20%) (Woolsey et al. 2003). The available information about the mechanisms of amastigote penetration is comparatively scarcer than that of trypomastigotes. In studies on interactions with macrophages, it has been noted that members of the Gp85/TS antigen family engage mannose receptors to gain entry to professional phagocytes (Kahn et al. 1995). Carbohydrate epitopes seem to play a role in the initial steps of invasion in non-phagocytic cells (Silva et al. 2006). The relative roles of PI3-K, endosomal trafficking and LAMP-1 (Procópio et al. 1998) pathways in extracellular amastigote invasion are still not fully understood.

After entering host cells, parasites are usually found in an acidic membrane-bound compartment referred to as phagosome or PV, that may be comprised of host cell plasma membrane, or endosomal or lysosomal in its origin (Milder & Kloetzel 1980, Meirelles et al. 1986, Carvalho & De Souza 1989, Hall et al. 1991, Schenkman & Mortara 1992, Wilkowsky et al. 2002, Woolsey et al. 2003, Andrade & Andrews 2004, Fernandes et al. 2007b). The time of residence inside the PVs may vary between infective forms, ranging from 1-2 h in the case of amastigotes and TCTs (Meirelles et al. 1986, Ley et al. 1990, Hall et al. 1992, Stecconi-Silva et al. 2003, Andrade & Andrews 2004, Rubin-de-Celis et al. 2006) to several hours in the case of MT trypomastigotes (Stecconi-Silva et al. 2003, Rubin-de-Celis et al. 2006). These then eventually escape and differentiate into amastigotes in the cytoplasm (De Souza 1984, 2000, 2005, Andrews 2000).

Once inside the host cells, trypomastigotes and amastigotes secrete TcTOX, a complement 9 (C9) factor-related molecule that, at low pH, will destroy the PV membrane and allow the parasite access to the cytosol (Andrews & Whitlow 1989, Andrews 1990, Andrews et al. 1990, Ley et al. 1990, Manning-Cela et al. 2001, Rubin-de-Celis et al. 2006). Raising the intracellular pH with weak bases affects MT invasion and substantially delays escape from the PV, increasing the latency from about 2-10 h. By contrast, the kinetics of amastigote invasion and escape are not affected by this treatment (Stecconi-Silva et al. 2003). This lytic activity is likely to be facilitated by parasite transialidase activity on the lumenal glycoproteins that protect the PV (Hall et al. 1992, Stecconi-Silva et al. 2003, Rubin-de-Celis et al. 2006). In agreement with the idea that the glycosylation of lysosomal lumenal glycoproteins is relevant for the protection of the PV membrane, parasites promptly escape from PVs formed in CHO cells deficient in sialylation (Stecconi-Silva et al. 2003, Rubin-de-Celis et al. 2006). So far, TcTOX activity has been observed in extracellular amastigotes (Ley et al. 1990, Stecconi-Silva et al. 2003) and TCTs (Manning-Cela et al. 2001, Andreoli & Mortara 2003, Rubin-de-Celis et al. 2006). In contrast, MT trypomastigotes display both very weak transialidase activity and undetectable TcTOX (Andreoli & Mortara 2003, Stecconi-Silva et al. 2003). Therefore, whereas extracellular TCTs and amastigotes display a somewhat predictable behaviour regarding cell invasion and escape, at present we do not have a consistent model to fully understand how MT trypomastigotes actually escape from their PVs. Using polyclonal antibodies to C9, it has recently been shown that amastigotes express a TcTOX-related compound (Andreoli et al. 2006); this tool may be useful for mapping this compound throughout the intracellular traffic in the different infective forms. Recent work has shown that the kinetics of endosomal and lysosomal marker accumulation, and their subsequent loss - indicative of parasite escape into the cytoplasm - is not correlated with either the infective form or phylogenetic group of the parasite tested under these particular conditions (Fernandes et al. 2007b).

Once free in the cytoplasm, trypomastigotes differentiate into amastigotes; these forms then begin to grow by binary fission for up to nine cycles (Dvorak & Hyde 1973). During the course of intracellular growth, the parasite disrupts host cellular structure, attachment to the substrate becomes loose and basic functions such as contractility are impaired (Meyer & Xavier de Oliveira 1948, Dvorak & Hyde 1973, Low et al. 1992, Pereira et al. 1993, 2000, Carvalho et al. 1999, Hall et al. 2000, Taniwaki et al. 2005, 2006). Usually, with the cytoplasm loaded with a couple of tens of amastigotes, host cell division becomes arrested (Meyer & Xavier de Oliveira 1948, Low et al. 1992). During the differentiation of amastigotes into trypomastigotes, preceding cell rupture and the release of the parasite into the surrounding medium, intermediate epimastigote-like forms have been observed (Meyer & Xavier de Oliveira 1948, Almeida-de-Faria et al. 1999, Tonelli et al. 2004). When the cell becomes filled with trypomastigotes, the plasma membrane ruptures and significant degenerative processes can be observed, probably due to the intense mechanical movement of the parasites (Meyer & Xavier de Oliveira 1948, Low et al. 1992, Pereira et al. 1993, Taniwaki et al. 2005, 2006). Interestingly, the intracellular cell cycle of T. cruzi seems to be independent of the of the host cell nucleus, as all developmental stages can be found within enucleated host cells infected with trypomastigotes (Coimbra et al. 2007). Although the precise mechanism underlying cell rupture has been inferred as being mostly mechanical in nature, it has been known since the original studies by Hertha Meyer that different cell types present distinct susceptibilities to cellular rupture by the intracellular parasites (Meyer 1942, Meyer & Xavier de Oliveira 1948).

The precise mechanisms that govern the intricate signalling exchanges between the parasite and the host cell are discussed in a separate section. As indicated above, several studies have found that amastigotes, prematurely released from infected cells or generated by the extracellular differentiation of released TCTs, can also infect cultured cells and animals (Behbehani 1973, Nogueira & Cohn 1976, Hudson et al. 1984, Carvalho & De Souza 1986, Ley et al. 1988, Mortara 1991). Systematic studies on cell invasion and PV escape carried out in several laboratories have reinforced the notion that each infective form of the parasite has a unique interplay with the specific target host cell with which it interacts. Not only the parasite infective form, but also the strain (and phylogenetic origin) will determine the outcome of this interaction (Milder & Kloetzel 1980, Carvalho & De Souza 1986, 1989, Meirelles et al. 1986, Ley et al. 1990, Hall et al. 1992, Andrews 1994, Ochatt et al. 1997, Stecconi-Silva et al. 2003, Rubin-de-Celis et al. 2006, Fernandes et al. 2007b). The variety of mechanisms used for cell invasion and escape from the PVs by amastigotes and trypomastigotes is consistent with the complex repertoires of both infective forms and surface molecules that the parasite has evolved to ensure host colonisation (Ley et al. 1990, Hall et al. 1992, Andrews 1994, Yoshida 2002, Mortara et al. 2005, Yoshida & Cortez 2008, da Silva et al. 2009). Adding to this already complex scenario, less canonical host cell invasion mechanisms should also be mentioned. These include the phagocytosis of apoptotic T. cruzi infected lymphocytes (Freire-de-Lima et al. 2000, Luder et al. 2001, Lopes et al. 2007, De Meis et al. 2008) and the less-studied autophagic pathway (Romano et al. 2009). It is similarly worth mentioning that there are a variety of receptors linked to the host immune system, such as Toll-like receptors that parasite molecules engage with during in vivo infections, and which therefore may also play a key role in the host-parasite interplay (Tarleton 2007).

Signalling mechanisms and molecules involved in T. cruzi invasion

The number of identified interacting components that may play a role in T. cruzi-host cell interactions is continually growing. For recent reviews on this rapidly evolving field, the reader is referred to the following references: De Souza (2000, 2002), Burleigh and Woolsey (2002), Yoshida (2002), Andrade and Andrews (2005), Mortara et al. (2005), Alves and Colli (2007), Scharfstein and Lima (2008), Yoshida and Cortez (2008). Multiple interactions between molecules from the parasite and the host lead to the internalisation of the parasite and an increase of cytosolic Ca²⁺ in both the host cells and in the parasite during invasion (Morris et al. 1988, Moreno et al. 1992, 1994, Krassner et al. 1993, Burleigh & Andrews 1995b, 1998, Docampo et al. 1995, Dorta et al. 1995, Wilkowsky et al. 1996). From the point of view of various types of host cell, contact with TCTs (Tardieux et al. 1994), MTs (Dorta et al. 1995) and extracellular amastigotes (Fernandes et al. 2006), but not epimasti-gotes (Tardieux et al. 1994), gives rise to a transient calcium influx. The same phenomena was observed when either specific molecules involved in T. cruzi cell invasion or uncharacterised factors released by the parasite (Tardieux et al. 1994, Burleigh & Andrews 1995a) were incubated with the host cell.

Calcium influxes have been associated with the formation of PVs or with parasite evasion from the vacuoles and successful infection (Burleigh & Andrews 1998, Burleigh & Woolsey 2002, De Souza 2002, Andrade & Andrews 2004, Burleigh 2005). Among the T. cruzi components involved in invasion are molecules belonging to the Gp85/trans-sialidase superfamily (Gp85/TS) and mucin-like proteins present on the surface of the parasite. Both are encoded by large gene families (~1430 and ~863 gp85/TS and mucin-encoding genes, respectively) (Colli 1993, Frasch 1994, Schenkman et al. 1994). As interesting examples, members of the Gp85/TS family are developmentally regulated by postranscriptional mechanisms, with Gp82 and Tc85 glycoproteins expressed mainly in the MT and TCT forms, respectively. Gp82 binds to gastric mucin and Tc85 binds to members of the laminin and fibronectin families in the extracellular matrix (ECM); however, other receptors cannot be ruled out as Tc85 molecules have been described as multi-adhesion glycoproteins (Wirth & Kierszenbaum 1984, Ouaissi et al. 1984, 1985, Noisin & Villalta 1989, Santana et al. 1997, Magdesian et al. 2001, Ulrich et al. 2002, Nde et al. 2006, Yoshida 2008). It should be mentioned that other molecules expressed in T. cruzi bind to ECM elements such as heparin, heparan sulfate, collagen and thrombospondin-1 (Ortega-Barria & Pereira 1991). A synthetic peptide based on the conserved FLY domain (VTVXNVFLYNR) present in all members of the Gp85/TS family promotes dephosphorylation of an intermediate filament protein (cytokeratin 18) that leads to cytoskeleton reorganisation and activation of the ERK1/2 signalling cascade; as a result, there is an increase in the entry of parasites into epithelial cells (Magdesian et al. 2007). On the other hand, it has been shown that an inactive form of TS from TCT that binds sialic acid triggers NF-kB activation, the expression of adhesion molecules on endothelial cells and upregulation of parasite entry in a FLY-independent and carbohydrate-dependent way (Dias et al. 2008). Recently, TS has been linked to the invasion of TrkA (nerve growth factor receptor)-expressing cells (e.g., dendritic cells) by a mechanism that involves triggering TrkA-dependent and PI3-K/AkT kinase signalling events (Melo-Jorge & Pereira-Perrin 2007). The presence of Gp82 on MT trypomastigotes induces calcium transients that result in phosphorylation of a 175 kDa protein in MTs (CL strain) and Ca²⁺ mobilisation in the host cell through a sequence of events involving PTK, PLC and IP3 (Yoshida 2006, 2008, Yoshida & Cortez 2008). Interestingly, although gp35/50 mucins are the main MT surface components involved in the attachment phase of the G strain of T. cruzi (Ruiz et al. 1993) and Gp85/35 mucins are important acceptors of sialic acid catalysed by trans-sialidase, sialyl residues (Schenkman et al. 1993) are not involved in the invasion mechanism (Yoshida et al. 1997). On the other hand, the role of sialic acid in TCT invasion, together with other lectin-like interactions, has yet to be fully clarified (Libby et al. 1986, Ming et al. 1993, Schenkman et al. 1993, 1994, Yoshida et al. 1997, Stecconi-Silva et al. 2003, Rubin-de-Celis et al. 2006, Dias et al. 2008).

Another mechanism for the attachment-independent invasion of trypomastigotes phase involves the activation of the TGFβ signalling pathway (Silva et al. 1991, Ming et al. 1995, Araujo-Jorge et al. 2008). The agent involved in mediating the signalling remains elusive, but it seems to be thermo-labile and hydrophobic in nature. It is likely that a protease secreted by the parasite might activate latent TGFβ-associated with ECM components, allowing activation of Smad 2/3 pathway through the TGFβ receptors (I and II) present on the surface of host cells. The pivotal role of this pathway in infectious of heart tissues and consequently in the chagasic myocardiopathy has been described (Araujo-Jorge et al. 2008).

Other molecules not involved directly in receptor-ligand interactions are nonetheless fundamental to establishing infection by T. cruzi. Inhibitors of the prolyl oligopeptidase (POP Tc80), a serine protease that hydrolyses human collagens types I and IV and fibronectin blocks the entry of TCTs into cultured cells (Harth et al. 1993, Santana et al. 1997, Grellier et al. 2001). Cruzipain, the major cysteine protease present in all stages of T. cruzi, has also been implicated in the internalisation process due to its ability to generate bradykinin and increase parasite entry through B2-type bradykinin receptors. A link between innate and adaptive immune responses through bradykinin has therefore been proposed. It is worth mentioning in this context that the invasion of host cells by MTs of the CL strain depends on tyrosine phosphorylation and the IP₃-dependent (1,4,5-inositol-triphosphate) release of calcium from endoplasmic reticulum (ER) stores, whereas MTs of the G strain engage adenylate cyclase and cause calcium to be mobilised from acidocalcisomes (Neira et al. 2002). No comparative data between both strains is evaluable for TCTs, but inhibitors of class I and class III PI3-K activities block the entry of the parasite into macrophages, suggesting the involvement of different isoforms of this kinase (Todorov et al. 2000). On the other hand, it seems that calcium mobilisation from acidocalcisomes, but not from the ER, is important for cellular invasion by extracellular amastigotes of either the G or CL strains (Mortara et al. 2005, Fernandes et al. 2006, Scharfstein et al. 2007, 2008, Scharfstein & Lima 2008).

A lot of attention was initially given to the signalling pathways active inside the host cell during T. cruzi infection, as well as to the identification of ligands and receptors involved in the infection process. Although a great deal has been learned from sequencing the T. cruzi genome (El Sayed et al. 2005a, b), including mapping its 190 kinases and 86 phosphatases (Parsons et al. 2005, Brenchley et al. 2007), knowledge about the signalling pathways active in the parasite is still scarce and, mostly, fragmented. It is evident that the complexity of the system has yet to be overcome.

Perspectives

It is clear that the mechanisms of invasion used by T. cruzi TCTs, MT trypomastigotes and extracellular amastigotes are divergent. Adding to this complexity is the finding that there are mechanistic variations between isolates of the two main phylogenetic groups that also depend on the type of host cell analysed. To circumvent this issue, specific host lineages and T. cruzi strains and/or clones could be chosen as models to be used by the scientific community in order to reveal urgently needed information about the general mechanisms that govern mammalian cell invasion.

A great deal more research has been done to establish the signalling pathways in the host cells than in the parasite during infection. The 190 kinases and 86 phosphatases identified in the T. cruzi genome should, hopefully, provide the necessary tools to increase interest in the field and provide more complete mechanistic explanations of the infection process.

REFERENCES

• Alcantara A, Brener Z 1978. The in vitro interaction of Trypanosoma cruzi bloodstream forms and mouse peritoneal macrophages. Acta Trop 35: 209-219.
• Alcantara A, Brener Z 1980. Trypanosoma cruzi: role of macrophage membrane components in the phagocytosis of bloodstream forms. Exp Parasitol 50: 1-6.
• Alexander J 1975. Effect of the antiphagocytic agent cytochalasin B on macrophage invasion by Leishmania mexicana promastigotes and Trypanosoma cruzi epimastigotes. J Protozool 22: 237-240.
• Almeida-de-Faria M, Freymuller E, Colli W, Alves MJ 1999. Trypanosoma cruzi: characterization of an intracellular epimasti-gote-like form. Exp Parasitol 92: 263-274.
• Almeida IC, Gazzinelli RT 2001. Proinflammatory activity of glycosylphosphatidylinositol anchors derived from Trypanosoma cruzi: structural and functional analyses. J Leukoc Biol 70: 467-477.
• Alves MJ, Colli W 1974. Agglutination of Trypanosoma cruzi by concanavalin A. J Protozool 21: 575-578.
• Alves MJ, Colli W 2007. Trypanosoma cruzi: adhesion to the host cell and intracellular survival. IUBMB Life 59: 274-279.
• Alves MJ, Colli W 2008. Role of the gp85/trans-sialidase superfamily of glycoproteins in the interaction of Trypanosoma cruzi with host structures. Subcell Biochem 47: 58-69.
• Alves MJM, Abuin G, Kuwajima VY, Colli W 1986. Partial inhibition of trypomastigote entry into cultured mammalian cells by monoclonal antibodies against a surface glycoprotein of Trypanosoma cruzi. Mol Biochem Parasitol 21: 75-82.
• Alves MJM, Colli W 1975. Glycoproteins from Trypanosoma cruzi: partial purification by gel chromatography. FEBS Lett 52: 188-190.
• Andrade AFB, Esteves MJG, Angluster J, Gonzales-Perdomo M, Goldenberg S 1991. Changes in cell-surface carbohydrates of Trypanosoma cruzi during metacyclogenesis under chemically defined conditions. J Gen Microbiol 137: 2845-2849.
• Andrade LO, Andrews NW 2004. Lysosomal fusion is essential for the retention of Trypanosoma cruzi inside host cells. J Exp Med 200: 1135-1143.
• Andrade LO, Andrews NW 2005. The Trypanosoma cruzi-host-cell interplay: location, invasion, retention. Nat Rev Microbiol 3: 819-823.
• Andreoli WK, Mortara RA 2003. Acidification modulates the traffic of Trypanosoma cruzi trypomastigotes in Vero cells harboring Coxiella burnetti vacuoles. Int J Parasitol 33: 185-197.
• Andreoli WK, Taniwaki NN, Mortara RA 2006. Survival of Trypanosoma cruzi metacyclic trypomastigotes within Coxiella burnetii vacuoles: differentiation and replication within an acidic milieu. Microbes Infect 8: 172-182.
• Andrews NW 1990. The acid-active hemolysin of Trypanosoma cruzi. Exp Parasitol 71: 241-244.
• Andrews NW 1994. From lysosomes into the cytosol: the intracellular pathway of Trypanosoma cruzi. Braz J Med Biol Res 27: 471-475.
• Andrews NW 1995. Lysosome recruitment during host cell invasion by Trypanosoma cruzi. Trends Cell Biol 5: 133-137.
• Andrews NW 2000. Regulated secretion of conventional lysosomes. Trends Cell Biol 10: 316-321.
• Andrews NW 2002. Lysosomes and the plasma membrane: trypanosomes reveal a secret relationship. J Cell Biol 158: 389-394.
• Andrews NW, Abrams CK, Slatin SL, Griffiths G 1990. A T. cruzi-secreted protein immunologically related to the complement component C9: evidence for membrane pore-forming activity at low pH. Cell 61: 1277-1287.
• Andrews NW, Colli W 1982. Adhesion and interiorization of Trypanosoma cruzi in mammalian cells. J Protozool 29: 264-269.
• Andrews NW, Katzin AM, Colli W 1984. Mapping of surface glycoproteins of Trypanosoma cruzi by two- dimensional electrophoresis. A correlation with the cell invasion capacity. Eur J Biochem 140: 599-604.
• Andrews NW, Robbins ES, Ley V, Hong KS, Nussenzweig V 1988. Developmentally regulated, phospholipase C-mediated release of the major surface glycoprotein of amastigotes of Trypanosoma cruzi. J Exp Med 167: 300-314.
• Andrews NW, Whitlow MB 1989. Secretion by Trypanosoma cruzi of a hemolysin active at low pH. Mol Biochem Parasitol 33: 249-256.
• Aoki T, Nakajima-Shimada J, Hirota Y 1995. Quantitative determination of Trypanosoma cruzi growth inside host cells in vitro and effect of allopurinol. Adv Exp Med Biol 370: 499-502.
• Aprigliano O, Masuda MO, Meirelles MN, Pereira MC, Barbosa HS, Barbosa JC 1993. Heart muscle cells acutely infected with Trypanosoma cruzi: characterization of electrophysiology and neurotransmitter responses. J Mol Cell Cardiol 25: 1265-1274.
• Araujo-Jorge TC 1989. The biology of Trypanosoma cruzi-macrophage interaction. Mem Inst Oswaldo Cruz 84: 441-462.
• Araujo-Jorge TC, De Souza W 1984. Effect of carbohydrates, periodate and enzymes in the process of endocytosis of Trypanosoma cruzi by macrophages. Acta Trop 41: 17-28.
• Araujo-Jorge TC, Waghabi MC, Soeiro MN, Keramidas M, Bailly S, Feige JJ 2008. Pivotal role for TGF-beta in infectious heart disease: the case of Trypanosoma cruzi infection and consequent Chagasic myocardiopathy. Cytokine Growth Factor Rev 19: 405-413.
• Atayde VD, Neira I, Cortez M, Ferreira D, Freymuller E, Yoshida N 2004. Molecular basis of non-virulence of Trypanosoma cruzi clone CL-14. Int J Parasitol 34: 851-860.
• Atwood JA, III, Weatherly DB, Minning TA, Bundy B, Cavola C, Opperdoes FR, Orlando R, Tarleton RL 2005. The Trypanosoma cruzi proteome. Science 309: 473-476.
• Avila JL, Rojas M, Galili U 1989. Immunogenic Gal alpha 1-3Gal carbohydrate epitopes are present on pathogenic American Trypanosoma and Leishmania. J Immunol 142: 2828-2834.
• Baida RC, Santos MR, Carmo MS, Yoshida N, Ferreira D, Ferreira AT, El Sayed NM, Andersson B, Da Silveira JF 2006. Molecular characterization of serine-alanine- and proline-rich proteins of Trypanosoma cruzi and their possible role in host cell infection. Infect Immun 74: 1537-1546.
• Baker JR, Price J 1973. Growth in vitro of Trypansoma cruzi as amastigotes at temperatures below 37ºC. Int J Parasitol 3: 549-551.
• Barrias ES, Dutra JM, De Souza W, Carvalho TM 2007. Participation of macrophage membrane rafts in Trypanosoma cruzi invasion process. Biochem Biophys Res Commun 363: 828-834.
• Bartholomeu DC, Ropert C, Melo MB, Parroche P, Junqueira CF, Teixeira SM, Sirois C, Kasperkovitz P, Knetter CF, Lien E, Latz E, Golenbock DT, Gazzinelli RT 2008. Recruitment and endo-lysosomal activation of TLR9 in dendritic cells infected with Trypanosoma cruzi. J Immunol 181: 1333-1344.
• Behbehani K 1973. Developmental cycles of Trypanosoma (Schyzotrypanum) cruzi (Chagas, 1909) in mouse peritoneal macrophages in vitro. Parasitology 66: 343-353.
• Bertello LE, Andrews NW, Lederkremer RM 1996. Developmentally regulated expression of ceramide in Trypanosoma cruzi. Mol Biochem Parasitol 79: 143-151.
• Bice DE, Zeledon R 1970. Comparison of infectivity of strains of Trypanosoma cruzi (Chagas 1909). J Parasitol 54: 663-670.
• Brenchley R, Tariq H, McElhinney H, Szoor B, Huxley-Jones J, Stevens R, Matthews K, Tabernero L 2007. The TriTryp phosphatome: analysis of the protein phosphatase catalytic domains. BMC Genomics 8: 434.
• Brener Z 1969. The behaviour of slender and stout forms of Trypanosoma cruzi in the bloodstream of normal and immune mice. Ann Trop Med Parasitol 63: 215-220.
• Brener Z 1977. Intraspecific variations in Trypanosoma cruzi: two types of parasite populations presenting distinct characteristics. Pan Am Health Organ Sci Publ 347: 11-21.
• Briones MR, Souto RP, Stolf BS, Zingales B 1999. The evolution of two Trypanosoma cruzi subgroups inferred from rRNA genes can be correlated with the interchange of American mammalian faunas in the Cenozoic and has implications to pathogenicity and host specificity. Mol Biochem Parasitol 104: 219-232.
• Brisse S, Dujardin JC, Tibayrenc M 2000. Identification of six Trypanosoma cruzi lineages by sequence-characterised amplified region markers. Mol Biochem Parasitol 111: 95-105.
• Burleigh BA 2005. Host cell signaling and Trypanosoma cruzi invasion: do all roads lead to lysosomes? Sci STKE: e36.
• Burleigh BA, Andrews NW 1995a. A 120-kDa alkaline peptidase from Trypanosoma cruzi is involved in the generation of a novel Ca²⁺-signaling factor for mammalian cells. J Biol Chem 270: 5172-5180.
• Burleigh BA, Andrews NW 1995b. The mechanisms of Trypanosoma cruzi invasion of mammalian cells. Annu Rev Microbiol 49: 175-200.
• Burleigh BA, Andrews NW 1998. Signaling and host cell invasion by Trypanosoma cruzi. Curr Opin Microbiol 1: 461-465.
• Burleigh BA, Caler EV, Webster P, Andrews NW 1997. A cytosolic serine endopeptidase from Trypanosoma cruzi is required for the generation of Ca²⁺ signaling in mammalian cells. J Cell Biol 136: 609-620.
• Burleigh BA, Woolsey AM 2002. Cell signalling and Trypanosoma cruzi invasion. Cell Microbiol 4: 701-711.
• Caler EV, Chakrabarti S, Fowler KT, Rao S, Andrews NW 2001. The exocytosis-regulatory protein synaptotagmin VII mediates cell invasion by Trypanosoma cruzi. J Exp Med 193: 1097-1104.
• Caler EV, Morty RE, Burleigh BA, Andrews NW 2000. Dual role of signaling pathways leading to Ca⁽²⁺⁾ and cyclic AMP elevation in host cell invasion by Trypanosoma cruzi. Infect Immun 68: 6602-6610.
• Camargo EP 1964. Growth and differentiation in Trypanosoma cruzi: origin of metacyclic trypomastigotes in liquid media. Rev Inst Med Trop Sao Paulo 6: 93-100.
• Carvalho RMG, Meirelles MNL, De Souza W, Leon W 1981. Isolation of the intracellular stage of Trypanosoma cruzi and its interaction with mouse macrophages in vitro. Infect Immun 33: 546-554.
• Carvalho TM, De Souza W 1986. Infectivity of amastigotes of Trypanosoma cruzi. Rev Inst Med Trop Sao Paulo 28: 205-212.
• Carvalho TM, De Souza W 1989. Early events related with the behavior of Trypanosoma cruzi within an endocytic vacuole in mouse peritoneal macrophages. Cell Struct Funct 14: 383-392.
• Carvalho TM, Ferreira AG, Coimbra ES, Rosestolato CT, De Souza W 1999. Distribution of cytoskeletal structures and organelles of the host cell during evolution of the intracellular parasitism by Trypanosoma cruzi. J Submicrosc Cytol Pathol 31: 325-333.
• Chagas C 1909. Nova tripanozomíase humana. Estudos sobre a morfologia e o ciclo evolutivo do Schizotrypanum n.gen, n. sp., agente etiológico de nova entidade mórbida do homem. Mem Inst Oswaldo Cruz 1: 159-218.
• Chagas C 1911. Nova entidade morbida do homem. Resumo geral de estudos etiologicos e clínicos. Mem Inst Oswaldo Cruz 3: 219-275.
• Chaves LB, Briones MRS, Schenkman S 1993. Trans-sialidase from Trypanosoma cruzi epimastigotes is expressed at the stationary phase and is different from the enzyme expressed in trypomastigotes. Mol Biochem Parasitol 61: 97-106.
• Chuenkova M, Pereira MEA 1995. Trypanosoma cruzi trans-sialidase: enhancement of virulence in a murine model of Chagas' disease. J Exp Med 181: 1693-1703.
• Chuenkova MV, Pereira MA 2001. The T. cruzi trans-sialidase induces PC12 cell differentiation via MAPK/ERK pathway. Neuroreport 12: 3715-3718.
• Coimbra VC, Yamamoto D, Khusal KG, Atayde VD, Fernandes MC, Mortara RA, Yoshida N, Alves MJ, Rabinovitch M 2007. Enucleated L929 cells support invasion, differentiation and multiplication of Trypanosoma cruzi parasites. Infect Immun 75: 3700-3706.
• Colli W 1984. Interiorization of Trypanosoma cruzi into mammalian host cells in the light of the parasite membrane chemical composition. Mem Inst Oswaldo Cruz 79: 45-50.
• Colli W 1993. Trans-sialidase: a unique enzyme activity discovered in the protozoan Trypanosoma cruzi. FASEB J 7: 1257-1264.
• Cortez M, Atayde V, Yoshida N 2006. Host cell invasion mediated by Trypanosoma cruzi surface molecule gp82 is associated with F-actin disassembly and is inhibited by enteroinvasive Escherichia coli. Microbes Infect 8: 1502-1512.
• Couto AS, De Lederkremer RM, Colli W, Alves MJM 1993. The glycosylphosphatidylinositol anchor of the trypomastigote- specific Tc-85 glycoprotein from Trypanosoma cruzi--metabolic- labeling and structural studies. Eur J Biochem 217: 597-602.
• Couto AS, Gonçalves MF, Colli W, Lederkremer RM 1990. The N-linked carbohydrate chain of the 85-kilodalton glycoprotein from Trypanosoma cruzi trypomastigotes contains sialyl, fucosyl and galactosyl (alpha 1-3) galactose units. Mol Biochem Parasitol 39: 101-107.
• Cross GAM, Takle GB 1993. The surface trans-sialidase family of Trypanosoma cruzi. Annu Rev Microbiol 47: 385-411.
• da Silva CV, Kawashita SY, Probst CM, Dallagiovanna B, Cruz MC, Silva EA, Souto-Padrón T, Krieger MA, Goldenberg S, Briones MRS, Andrews NW, Mortara RA 2009. Characterization of a 21 kDa protein from Trypanosoma cruzi associated with mammalian cell invasion. Microbes Infect, in press.
• de Lederkremer RM, Casal OL, Alves MJ, Colli W 1980. Evidence for the presence of D-galactofuranose in the lipopeptidophosphoglycan from Trypanosome cruzi. Modification and tritium labeling. FEBS Lett 116: 25-29.
• de Lederkremer RM, Colli W 1995. Galactofuranose-containing glycoconjugates in trypanosomatids. Glycobiology 5: 547-552.
• De Meis J, Ferreira LM, Guillermo LV, Silva EM, Dosreis GA, Lopes MF 2008. Apoptosis differentially regulates mesenteric and subcutaneous lymph node immune responses to Trypanosoma cruzi. Eur J Immunol 38: 139-146.
• De Souza W 1984. Cell biology of Trypanosoma cruzi. Int Rev Cell Biol 86: 197-283.
• De Souza W 2000. O parasito e sua interação com os hospedeiros. In Trypanosoma cruzi e doença de Chagas. Z Brener, ZA Andrade, M Barral-Netto (eds.), Guanabara Koogan, Rio de Janeiro, p. 88-126.
• De Souza W 2002. Basic cell biology of Trypanosoma cruzi. Curr Pharm Des 8: 269-285.
• De Souza W 2005. Microscopy and cytochemistry of the biogenesis of the parasitophorous vacuole. Histochem Cell Biol 123: 1-18.
• De Souza W 2008. Electron microscopy of trypanosomes - a historical view. Mem Inst Oswaldo Cruz 103: 313-325.
• de Titto EH, Araujo FG 1987. Mechanism of cell invasion by Trypanosoma cruzi: importance of sialidase activity. Acta Trop 44: 273-282.
• Devera R, Fernandes O, Coura JR 2003. Should Trypanosoma cruzi be called "cruzi" complex? A review of the parasite diversity and the potential of selecting population after in vitro culturing and mice infection. Mem Inst Oswaldo Cruz 98: 1-12.
• Dias WB, Fajardo FD, Graca-Souza AV, Freire-de-Lima L, Vieira F, Girard MF, Bouteille B, Previato JO, Mendonca-Previato L, Todeschini AR 2008. Endothelial cell signalling induced by trans-sialidase from Trypanosoma cruzi. Cell Microbiol 10: 88-99.
• Docampo R, Scott DA, Vercesi AE, Moreno SNJ 1995. Intracellular Ca²⁺ storage in acidocalcisomes of Trypanosoma cruzi. Biochem J 310: 1005-1012.
• Dorta ML, Ferreira AT, Oshiro MEM, Yoshida N 1995. Ca²⁺ signal induced by Trypanosoma cruzi metacyclic trypomastigote surface molecules implicated in mammalian cell invasion. Mol Biochem Parasitol 73: 285-289.
• Dvorak JA, Howe CL 1976. The attraction of Trypanosoma cruzi to vertebrate cells in vitro. J Protozool 23: 534-537.
• Dvorak JA, Hyde TP 1973. Trypanosoma cruzi: interaction with vertebrate cells in vitro. Individual interactions at the cellular and subcellular levels. Exp Parasitol 34: 268-283.
• Eakin AE, Mills AA, Harth G, McKerrow JH, Craik CS 1992. The sequence, organization and expression of the major cysteine protease (cruzain) from Trypanosoma cruzi. J Biol Chem 267: 7411-7420.
• El Sayed NM, Myler PJ, Bartholomeu DC, Nilsson D, Aggarwal G, Tran AN, Ghedin E, Worthey EA, Delcher AL, Blandin G, Westenberger SJ, Caler E, Cerqueira GC, Branche C, Haas B, Anupama A, Arner E, Aslund L, Attipoe P, Bontempi E, Bringaud F, Burton P, Cadag E, Campbell DA, Carrington M, Crabtree J, Darban H, Da Silveira JF, de Jong P, Edwards K, Englund PT, Fazelina G, Feldblyum T, Ferella M, Frasch AC, Gull K, Horn D, Hou L, Huang Y, Kindlund E, Klingbeil M, Kluge S, Koo H, Lacerda D, Levin MJ, Lorenzi H, Louie T, Machado CR, McCulloch R, McKenna A, Mizuno Y, Mottram JC, Nelson S, Ochaya S, Osoegawa K, Pai G, Parsons M, Pentony M, Pettersson U, Pop M, Ramirez JL, Rinta J, Robertson L, Salzberg SL, Sanchez DO, Seyler A, Sharma R, Shetty J, Simpson AJ, Sisk E, Tammi MT, Tarleton R, Teixeira S, Van Aken S, Vogt C, Ward PN, Wickstead B, Wortman J, White O, Fraser CM, Stuart KD, Andersson B 2005a. The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 309: 409-415.
• El Sayed NM, Myler PJ, Blandin G, Berriman M, Crabtree J, Aggarwal G, Caler E, Renauld H, Worthey EA, Hertz-Fowler C, Ghedin E, Peacock C, Bartholomeu DC, Haas BJ, Tran AN, Wortman JR, Alsmark UC, Angiuoli S, Anupama A, Badger J, Bringaud F, Cadag E, Carlton JM, Cerqueira GC, Creasy T, Delcher AL, Djikeng A, Embley TM, Hauser C, Ivens AC, Kummerfeld SK, Pereira-Leal JB, Nilsson D, Peterson J, Salzberg SL, Shallom J, Silva JC, Sundaram J, Westenberger S, White O, Melville SE, Donelson JE, Andersson B, Stuart KD, Hall N 2005b. Comparative genomics of trypanosomatid parasitic protozoa. Science 309: 404-409.
• Elias MC, Vargas N, Tomazi L, Pedroso A, Zingales B, Schenkman S, Briones MR 2005. Comparative analysis of genomic sequences suggests that Trypanosoma cruzi CL Brener contains two sets of non-intercalated repeats of satellite DNA that correspond to T. cruzi I and T. cruzi II types. Mol Biochem Parasitol 140: 221-227.
• Engel JC, Dvorak JA, Segura EL, Crane MSJ 1982. Trypanosoma cruzi: biological characterization of 19 clones derived from two chagasic patients. I. Growth kinetics in liquid medium. J Protozool 29: 555-560.
• Fernandes AB, Mortara RA 2004. Invasion of MDCK epithelial cells with altered expression of Rho GTPases by Trypanosoma cruzi amastigotes and metacyclic trypomastigotes of strains from the two major phylogenetic lineages. Microbes Infect 6: 460-467.
• Fernandes AB, Neira I, Ferreira AT, Mortara RA 2006. Cell invasion by Trypanosoma cruzi amastigotes of distinct infectivities: studies on signaling pathways. Parasitol Res 100: 59-68.
• Fernandes MC, Cortez M, Geraldo Yoneyama KA, Straus AH, Yoshida N, Mortara RA 2007a. Novel strategy in Trypanosoma cruzi cell invasion: implication of cholesterol and host cell microdomains. Int J Parasitol 37: 1431-1441.
• Fernandes MC, L'Abbate C, Kindro AW, Mortara RA 2007b. Trypanosoma cruzi cell invasion and traffic: influence of Coxiella burnetii and pH in a comparative study between distinct infective forms. Microb Pathog 43: 22-36.
• Ferreira D, Cortez M, Atayde VD, Yoshida N 2006. Actin cytoskeleton-dependent and -independent host cell invasion by Trypanosoma cruzi is mediated by distinct parasite surface molecules. Infect Immun 74: 5522-5528.
• Franke de Cazzulo BM, Martínez J, North MJ, Coombs GH, Cazzulo J-J 1994. Effects of proteinase inhibitors on the growth and differentiation of Trypanosoma cruzi. FEMS Microbiol Lett 124: 81-86.
• Frasch ACC 1994. Trans-sialidase, SAPA amino acid repeats and the relationship between Trypanosoma cruzi and the mammalian host. Parasitology 108 (Suppl.): S37-S44.
• Freire-de-Lima CG, Nascimento DO, Soares MB, Bozza PT, Castro-Faria-Neto HC, De Mello FG, Dos Reis GA, Lopes MF 2000. Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 403: 199-203.
• Frevert U, Schenkman S, Nussenzweig V 1992. Stage-specific expression and intracellular shedding of the cell surface trans-sialidase of Trypanosoma cruzi. Infect Immun 60: 2349-2360.
• Garg N, Postan M, Mensa-Wilmot K, Tarleton RL 1997. Glycosylphosphatidylinositols are required for the development of Trypanosoma cruzi amastigotes. Infect Immun 65: 4055-4060.
• Garzoni LR, Masuda MO, Capella MM, Lopes AG, Meirelles MN 2003. Characterization of [Ca²⁺]i responses in primary cultures of mouse cardiomyocytes induced by Trypanosoma cruzi trypomastigotes. Mem Inst Oswaldo Cruz 98: 487-493.
• Gaunt MW, Yeo M, Frame IA, Stothard JR, Carrasco HJ, Taylor MC, Mena SS, Veazey P, Miles GA, Acosta N, de Arias AR, Miles MA 2003. Mechanism of genetic exchange in American trypanosomes. Nature 421: 936-939.
• Gomes YM, Abath FGC, Furtado AF, Regis LN, Nakasawa M, Montenegro LT, Vouldoukis I, Alfred-Morin C, Monjour L 1995. A monoclonal antibody against blood forms of Trypanosoma cruzi lyses the parasite in vitro and inhibits host cell invasion. Appl Biochem Biotechnol 50: 57-70.
• Grellier P, Vendeville S, Joyeau R, Bastos IM, Drobecq H, Frappier F, Teixeira AR, Schrevel J, Davioud-Charvet E, Sergheraert C, Santana JM 2001. Trypanosoma cruzi prolyl oligopeptidase Tc80 is involved in nonphagocytic mammalian cell invasion by trypomastigotes. J Biol Chem 276: 47078-47086.
• Gutteridge WE, Cover B, Gaborak M 1978. Isolation of blood and intracellular forms of Trypanosoma cruzi from rats and other rodents and preliminary studies on their metabolism. Parasitology 76: 159-176.
• Hall BF, Furtado GC, Joiner KA 1991. Characterization of host cell-derived membrane proteins of the vacuole surrounding different intracellular forms of Trypanosoma cruzi in J774 cells: evidence for phagocyte receptor sorting during the early stages of parasite entry. J Immunol 147: 4313-4321.
• Hall BF, Webster P, Ma AK, Joiner KA, Andrews NW 1992. Desialylation of lysosomal membrane glycoproteins by Trypanosoma cruzi: a role for the surface neuraminidase in facilitating parasite entry into the host cell cytoplasm. J Exp Med 176: 313-325.
• Hall BS, Tam W, Sen R, Pereira ME 2000. Cell-specific activation of nuclear factor-kappaB by the parasite Trypanosoma cruzi promotes resistance to intracellular infection. Mol Biol Cell 11: 153-160.
• Harth G, Andrews NW, Mills AA, Engel JC, Smith R, McKerrow JH 1993. Peptide-fluoromethyl ketones arrest intracellular replication and intercellular transmission of Trypanosoma cruzi. Mol Biochem Parasitol 58: 17-24.
• Henriquez D, Piras R, Piras MM 1981. The effect of surface membrane modification of fibroblastic cells on the entry process of Trypanosoma cruzi trypomastigotes. Mol Biochem Parasitol 2: 359-366.
• Hoft DF 1996. Differential mucosal infectivity of different life stages of Trypanosoma cruzi. Am J Trop Med Hyg 55: 360-364.
• Hoft DF, Farrar PL, Kratz-Owens K, Shaffer D 1996. Gastric invasion by Trypanosoma cruzi and induction of protective mucosal immune responses. Infect Immun 64: 3800-3810.
• Howells RE, Chiari CA 1975. Observations on two strains of Trypanosoma cruzi in laboratory mice. Ann Trop Med Parasitol 69: 435-438.
• Huang H, Calderon TM, Berman JW, Braunstein VL, Weiss LM, Wittner M, Tanowitz HB 1999. Infection of endothelial cells with Trypanosoma cruzi activates NF- kappaB and induces vascular adhesion molecule expression. Infect Immun 67: 5434-5440.
• Hudson L, Snary D, Morgan SJ 1984. Trypanosoma cruzi: continuous cultivation with murine cell lines. Parasitology 88: 283-294.
• Junqueira AC, Degrave W, Brandao A 2005. Minicircle organization and diversity in Trypanosoma cruzi populations. Trends Parasitol 21: 270-272.
• Kahn S, Kahn M, Van Voorhis WC, Goshorn A, Strand A, Hoagland N, Eisen H, Pennathur S 1993. SA85-1 proteins of Trypanosoma cruzi lack sialidase activity. Mol Biochem Parasitol 60: 149-152.
• Kahn S, Wleklinski M, Aruffo A, Farr A, Coder D, Kahn M 1995. Trypanosoma cruzi amastigote adhesion to macrophages is facilitated by the mannose receptor. J Exp Med 182: 1243-1258.
• Kahn SJ, Wleklinski M, Ezekowitz RA, Coder D, Aruffo A, Farr A 1996. The major surface glycoprotein of Trypanosoma cruzi amastigotes are ligands of the human serum mannose-binding protein. Infect Immun 64: 2649-2656.
• Kipnis TL, Calich VL, Dias da Silva W 1979. Active entry of bloodstream forms of Trypanosoma cruzi into macrophages. Parasitology 78: 89-98.
• Krassner SM, Chang J, Pak S, Luc K-O, Granger B 1993. Absence of transitory [Ca²⁺]_i flux during early in vitro metacyclogenesis of Trypanosoma cruzi. J Protozool 40: 224-230.
• Krettli AU, Carrington PW, Nussenzweig RS 1979. Membrane-bound antibodies of bloodstream Trypanosoma cruzi in mice: strain differences in susceptibility to complement mediated lysis. Clin Exp Immunol 3: 1-8.
• Ley V, Andrews NW, Robbins ES, Nussenzweig V 1988. Amastigotes of Trypanosoma cruzi sustain an infective cycle in mammalian cells. J Exp Med 168: 649-659.
• Ley V, Robbins ES, Nussenzweig V, Andrews NW 1990. The exit of Trypanosoma cruzi from the phagosome is inhibited by raising the pH of acidic compartments. J Exp Med 171: 401-413.
• Libby P, Alroy J, Pereira MEA 1986. A neuraminidase from Trypanosoma cruzi removes sialic acid from the surface of mammalian myocardial and endothelial cells. J Clin Invest 77: 127-135.
• Lima MF, Kierszenbaum F 1982. Biochemical requirements for intracellular invasion by Trypanosoma cruzi: protein synthesis. J Protozool 29: 566-570.
• Lima MF, Villalta F 1988. Host-cell attachment by Trypanosoma cruzi: identification of an adhesion molecule. Biochem Biophys Res Commun 155: 256-262.
• Lopes MF, Guillermo LV, Silva EM 2007. Decoding caspase signaling in host immunity to the protozoan Trypanosoma cruzi. Trends Immunol 28: 366-372.
• Low HP, Paulin JJ, Keith CH 1992. Trypanosoma cruzi infection of BSC-1 fibroblast cells causes cytoskeletal disruption and changes in intracellular calcium levels. J Protozool 39: 463-470.
• Lu B, Alroy J, Luquetti AO, Pereira-Perrin M 2008. Human autoantibodies specific for neurotrophin receptors TrkA, TrkB and TrkC protect against lethal Trypanosoma cruzi infection in mice. Am J Pathol 173: 1406-1414.
• Luder CG, Gross U, Lopes MF 2001. Intracellular protozoan parasites and apoptosis: diverse strategies to modulate parasite-host interactions. Trends Parasitol 17: 480-486.
• Magdesian MH, Giordano R, Ulrich H, Juliano MA, Juliano L, Schumacher RI, Colli W, Alves MJM 2001. Infection by Trypanosoma cruzi: identification of a parasite ligand and its host-cell receptor. J Biol Chem 276: 19382-19389.
• Magdesian MH, Tonelli RR, Fessel MR, Silveira MS, Schumacher RI, Linden R, Colli W, Alves MJ 2007. A conserved domain of the gp85/trans-sialidase family activates host cell extracellular signal-regulated kinase and facilitates Trypanosoma cruzi infection. Exp Cell Res 313: 210-218.
• Malaga S, Yoshida N 2001. Targeted reduction in expression of Trypanosoma cruzi surface glycoprotein gp90 increases parasite infectivity. Infect Immun 69: 353-359.
• Manning-Cela R, Cortes A, Gonzalez-Rey E, Van Voorhis WC, Swindle J, Gonzalez A 2001. LYT1 protein is required for efficient in vitro infection by Trypanosoma cruzi. Infect Immun 69: 3916-3923.
• Manque PM, Eichinger D, Juliano MA, Juliano L, Araya JE, Yoshida N 2000. Characterization of the cell adhesion site of Trypanosoma cruzi metacyclic stage surface glycoprotein gp82. Infect Immun 68: 478-484.
• Mbawa ZR, Webster P, Lonsdale-Eccles JD 1991. Immunolocalization of a cysteine protease within the lysosomal system of Trypanosoma congolense. Eur J Cell Biol 56: 243-250.
• McKerrow JH 1991. New insights into the structure of a Trypanosoma cruzi protease. Parasitol Today 7: 132-133.
• Meirelles MNL, Araujo-Jorge TC, De Souza W 1982a. Interaction of Trypanosoma cruzi with macrophages in vitro: dissociation of the attachment and internalization phases by low temperature and cytochalasin B. Z Parasitenkd 68: 7-14.
• Meirelles MNL, Araujo-Jorge TC, De Souza W, Moreira AL, Barbosa HS 1987. Trypanosoma cruzi: phagolysosomal fusion after invasion into non professional phagocytic cells. Cell Struct Funct 12: 387-393.
• Meirelles MNL, Araujo-Jorge TC, Miranda CF, De Souza W, Barbosa HS 1986. Interaction of Trypanosoma cruzi with heart muscle cells: ultrastructural and cytochemical analysis of endocytic vacuole formation and effect upon myogenesis in vitro. Eur J Cell Biol 41: 198-206.
• Meirelles MNL, Chiari E, De Souza W 1982b. Interaction of bloodstream, tissue-culture-derived and axenic culture-derived trypomastigotes of Trypanosoma cruzi with macrophages. Acta Trop 39: 195-203.
• Meirelles MNL, Juliano L, Carmona E, Silva SG, Costa EM, Murta ACM, Scharfstein J 1992. Inhibitors of the major cysteinyl proteinase (GP57/51) impair host cell invasion and arrest the intracellular development of Trypanosoma cruzi in vitro. Mol Biochem Parasitol 52: 175-184.
• Meirelles MNL, Pereira MC, Singer RH, Soeiro MN, Garzoni LR, Silva DT, Barbosa HS, Araujo-Jorge TC, Masuda MO, Capella MA, Lopes AG, Vermelho AB 1999. Trypanosoma cruzi-cardiomyocytes: new contributions regarding a better understanding of this interaction. Mem Inst Oswaldo Cruz 94 (Suppl. I): 149-152.
• Melo RC, Brener Z 1978. Tissue tropism of different Trypanosoma cruzi strains. J Parasitol 64: 475-482.
• Melo TG, Almeida DS, Meirelles MNL, Pereira MCS 2004. Trypanosoma cruzi infection disrupts vinculin costamers in cardiomyocytes. Eur J Cell Biol 83: 531-540.
• Melo-Jorge M, Pereira-Perrin M 2007. The Chagas' disease parasite Trypanosoma cruzi exploits nerve growth factor receptor TrkA to infect mammalian hosts. Cell Host Microbe 1: 251-261.
• Meyer H 1942. Culturas de tecido nervoso infectadas por Szotrypanum cruzi. An Acad Bras Cienc 14: 253-256.
• Meyer H, Xavier de Oliveira M 1948. Cultivation of Trypanosoma cruzi in tissue cultures: a four- year study. Parasitology 39: 91-94.
• Milder RV, Kloetzel JK 1980. The development of Trypanosoma cruzi in macrophages in vitro. Interaction with lysosomes and host cell fate. Parasitology 80: 139-145.
• Miles MA 1974. Cloning Trypanosoma cruzi. Trans R Soc Trop Med Hyg 68: 256-260.
• Ming M, Chuenkova M, Ortega-Barria E, Pereira ME 1993. Mediation of Trypanosoma cruzi invasion by sialic acid on the host cell and trans-sialidase on the trypanosome. Mol Biochem Parasitol 59: 243-252.
• Ming M, Ewen ME, Pereira MEA 1995. Trypanosome invasion of mammalian cells requires activation of the TGFb signaling pathway. Cell 82: 287-296.
• Moreno SNJ, Silva J, Vercesi AE, Docampo R 1994. Cytosolic-free calcium elevation in Trypanosoma cruzi is required for cell invasion. J Exp Med 180: 1535-1540.
• Moreno SNJ, Vercesi AE, Pignataro OP, Docampo R 1992. Calcium homeostasis in Trypanosoma cruzi amastigotes: presence of inositol phosphates and lack of an inositol 1,4,5-trisphosphate- sensitive calcium pool. Mol Biochem Parasitol 52: 251-261.
• Morris SA, Tanowitz H, Hatcher V, Bilezikian JP, Wittner M 1988. Alterations in intracellular calcium following infection of human endothelial cells with Trypanosoma cruzi. Mol Biochem Parasitol 29: 213-221.
• Morris SA, Wittner M, Weiss L, Hatcher VB, Tanowitz HB, Bilezikian JP, Gordon PB 1990. Extracellular matrix derived from Trypanosoma cruzi infected endothelial cells directs phenotypic expression. J Cell Physiol 145: 340-346.
• Mortara RA 1991. Trypanosoma cruzi: amastigotes and trypomastigotes interact with different structures on the surface of HeLa cells. Exp Parasitol 73: 1-14
• Mortara RA, Andreoli WK, Fernandes MC, da Silva CV, Fernandes AB, L'Abbate C, Da Silva S 2008. Host cell actin remodeling in response to Trypanosoma cruzi: trypomastigote versus amasti-gote entry. Subcell Biochem 47: 101-109.
• Mortara RA, Andreoli WK, Taniwaki NN, Fernandes AB, Silva CV, Fernandes MC, L'Abbate C, Silva S 2005. Mammalian cell invasion and intracellular trafficking by Trypanosoma cruzi infective forms. An Acad Bras Cienc 77: 77-94.
• Mortara RA, Silva S, Araguth MF, Blanco SA, Yoshida N 1992. Polymorphism of the 35- and 50-kilodalton surface glycoconjugates of Trypanosoma cruzi metacyclic trypomastigotes. Infect Immun 60: 4673-4678.
• Nde PN, Simmons KJ, Kleshchenko YY, Pratap S, Lima MF, Villalta F 2006. Silencing of the laminin gamma-1 gene blocks Trypanosoma cruzi infection. Infect Immun 74: 1643-1648.
• Neira I, Ferreira AT, Yoshida N 2002. Activation of distinct signal transduction pathways in Trypanosoma cruzi isolates with differential capacity to invade host cells. Int J Parasitol 32: 405-414.
• Nogueira N 1983. Host and parasite factors affecting the invasion of mononuclear phagocytes by Trypanosoma cruzi. CIBA Found Symp 99: 52-73.
• Nogueira N, Cohn Z 1976. Trypanosoma cruzi: mechanism of entry and intracellular fate in mammalian cells. J Exp Med 143: 1402-1420.
• Noisin EL, Villalta F 1989. Fibronectin increases Trypanosoma cruzi amastigote binding to and uptake by murine macrophages and human monocytes. Infect Immun 57: 1030-1034.
• Ochatt CM, Mayorga LS, Isola EL, Wilkowsky S, Torres HN, Tellez-Iñon MT 1997. Inhibition of early endosome fusion by Trypanosoma cruzi-infected macrophage cytosol. J Euk Microbiol 44: 497-502.
• Ortega-Barria E, Pereira MEA 1991. A novel Trypanosoma cruzi heparin-binding protein promotes fibroblast adhesion and penetration of engineered bacteria and trypanosomes into mammalian cells. Cell 67: 411-421.
• Ouaissi MA, Afchain D, Capron A, Grimaud JA 1984. Fibronectin receptors on Trypanosoma cruzi trypomastigotes and their biological function. Nature 308: 380-382.
• Ouaissi MA, Cornette J, Capron A 1985. Trypanosoma cruzi: modulation of parasite-cell interaction by plasma fibronectin. Eur J Immunol 15: 1096-1101.
• Ouaissi MA, Taibi A, Loyens M, Martin U, Afchain D, Maidana C, Caudioti C, Cornette J, Martelleur A, Velge P, Marty B, Capron A 1991. Trypanosoma cruzi: a carbohydrate epitope defined by a monoclonal antibody as a possible marker of the acute phase of human chagas' disease. Am J Trop Med Hyg 45: 214-225.
• Pan SC 1978a. Trypanosoma cruzi: cultivation in macromolecule-free semisynthetic and synthetic media. Exp Parasitol 46: 108-112.
• Pan SCT 1978b. Trypanosoma cruzi: in vitro interactions between cultured amastigotes and human skin-muscle cells. Exp Parasitol 45: 274-286.
• Pan SC 1978c. Trypanosoma cruzi: ultrastructure of morphogenesis in vitro and in vivo. Exp Parasitol 46: 92-107.
• Parodi AJ, Labriola C, Cazzulo JJ 1995. The presence of complex-type oligosaccharides at the C-terminal domain glycosylation site of some molecules of cruzipain. Mol Biochem Parasitol 69: 247-255.
• Parodi AJ, Lederkremer GZ, Mendelzon DH 1983. Protein glycosylation in Trypanosoma cruzi. The mechanism of glycosylation and structure of protein-bound oligosaccharides. J Biol Chem 258: 5589-5595.
• Parodi AJ, Pollevick GD, Mautner M, Buschiazzo A, Sanchez DO, Frasch ACC 1992. A major Trypanosoma cruzi antigen has the unique trans-sialidase activity and the epitopes in separate domains. EMBO J 11: 1705-1710.
• Parsons M, Worthey EA, Ward PN, Mottram JC 2005. Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi. BMC Genomics 6: 127.
• Pereira MCS, Costa M, Chagas Filho C, De Meirelles MNL 1993. Myofibrillar breakdown and cytoskeletal alterations in heart muscle cells during invasion by Trypanosoma cruzi: immunological and ultrastructural study. J Submicrosc Cytol Pathol 25: 559-569.
• Pereira MCS, Singer RH, Meirelles MNL 2000. Trypanosoma cruzi infection affects actin mRNA regulation in heart muscle cells. J Euk Microbiol 47: 271-279.
• Pereira MEA 1983. A developmentally regulated neuraminidase activity in Trypanosoma cruzi. Science 219: 1444-1446.
• Petry K, Schottelius J, Baltz T 1987. Purification of metacyclic trypomastigotes of Trypanosoma cruzi and Trypanosoma dionisii from culture using an epimastigote-specific monoclonal antibody. Parasitol Res 73: 224-227.
• Piras MM, Henriquez D, Piras R 1985. The effect of proteolytic enzymes and protease inhibitors on the interaction Trypanosoma cruzi - fibroblasts. Mol Biochem Parasitol 14: 151-163.
• Piras MM, Henriquez D, Piras R 1987. The effect of fetuin and other sialoglycoproteins on the in vitro penetration of Trypanosoma cruzi trypomastigotes into fibroblastic cells. Mol Biochem Parasitol 22: 135-143.
• Piras R, Piras MM, Henriquez D 1982. The effect of inhibitors of macromolecular biosynthesis on the in vitro infectivity and morphology of Trypanosoma cruzi trypomastigotes. Mol Biochem Parasitol 6: 83-92.
• Piras R, Piras MM, Henriquez D 1983. Trypanosoma cruzi-fibroblastic cell interactions necessary for cellular invasion. CIBA Found Symp 99: 31-51.
• Poncini CV, Alba Soto CD, Batalla E, Solana ME, Gonzalez Cappa SM 2008. Trypanosoma cruzi induces regulatory dendritic cells in vitro. Infect Immun 76: 2633-2641.
• Previato JO, Andrade AF, Pessolani MC, Mendonça-Previato L 1985. Incorporation of sialic acid into Trypanosoma cruzi macromolecules A proposal for a new metabolic route. Mol Biochem Parasitol 16: 85-96.
• Previato JO, Jones C, Gonçalves LPB, Wait R, Travassos LR, Mendonça-Previato L 1994. O-glycosidically linked N-acetylglucosamine-bound oligosaccharides from glycoproteins of Trypanosoma cruzi. Biochem J 301: 151-159.
• Procópio DO, Barros HC, Mortara RA 1999. Actin-rich structures formed during the invasion of cultured cells by infective forms of Trypanosoma cruzi. Eur J Cell Biol 78: 911-924.
• Procópio DO, Silva S, Cunningham CC, Mortara RA 1998. Trypanosoma cruzi: effect of protein kinase inhibitors and cytoskeletal protein organization and expression on host cell invasion by amastigotes and metacyclic trypomastigotes. Exp Parasitol 90: 1-13.
• Robello C, Gamarro F, Castanys S, Alvarez-Valin F 2000. Evolutionary relationships in Trypanosoma cruzi: molecular phylogenetics supports the existence of a new major lineage of strains. Gene 246: 331-338.
• Rodriguez A, Martinez I, Chung A, Berlot CH, Andrews NW 1999. cAMP regulates Ca²⁺-dependent exocytosis of lysosomes and lysosome-mediated cell invasion by trypanosomes. J Biol Chem 274: 16754-16759.
• Rodriguez A, Webster P, Ortego J, Andrews NW 1997. Lysosomes behave as Ca²⁺-regulated exocytic vesicles in fibroblasts and epithelial cells. J Cell Biol 137: 93-104.
• Romano PS, Arboit MA, Vazquez CL, Colombo MI 2009. The autophagic pathway is a key component in the lysosomal dependent entry of Trypanosoma cruzi into the host cell. Autophagy 5: 6-18.
• Rubin-de-Celis SS, Uemura H, Yoshida N, Schenkman S 2006. Expression of trypomastigote trans-sialidase in metacyclic forms of Trypanosoma cruzi increases parasite escape from its parasitophorous vacuole. Cell Microbiol 8: 1888-1898.
• Ruiz RC, Rigoni VL, Gonzalez JC, Yoshida N 1993. The 35/50 kDa surface antigen of Trypanosoma cruzi metacyclic trypomastigotes, an adhesion molecule involved in host cell invasion. Parasite Immunol 15: 121-125.
• Santana JM, Grellier P, Schrevel J, Teixeira AR 1997. A Trypanosoma cruzi-secreted 80 kDa proteinase with specificity for human collagen types I and IV. Biochem J 325: 129-137.
• Santos CC, Sant'anna C, Terres A, Cunha-e-Silva NL, Scharfstein J, de Lima AP 2005. Chagasin, the endogenous cysteine-protease inhibitor of Trypanosoma cruzi, modulates parasite differentiation and invasion of mammalian cells. J Cell Sci 118: 901-915.
• Scharfstein J, Lima AP 2008. Roles of naturally occurring protease inhibitors in the modulation of host cell signaling and cellular invasion by Trypanosoma cruzi. Subcell Biochem 47: 140-154.
• Scharfstein J, Monteiro AC, Schmitz V, Svensjo E 2008. Angiotensin-converting enzyme limits inflammation elicited by Trypanosoma cruzi cysteine proteases: a peripheral mechanism regulating adaptive immunity via the innate kinin pathway. Biol Chem 389: 1015-1024.
• Scharfstein J, Schechter M, Senna M, Peralta JM, Mendonça-Previato L, Miles MA 1986. Trypanosoma cruzi: characterization and isolation of 57/51.000 m.w. surface glycoprotein (GP57/51) expressed in epimastigotes and bloodstream trypomastigotes. J Immunol 137: 1836-1842.
• Scharfstein J, Schmitz V, Morandi V, Capella MM, Lima AP, Morrot A, Juliano L, Muller-Esterl W 2000. Host cell invasion by Trypanosoma cruzi is potentiated by activation of bradykinin B(2) receptors. J Exp Med 192: 1289-1300.
• Scharfstein J, Schmitz V, Svensjo E, Granato A, Monteiro AC 2007. Kininogens coordinate adaptive immunity through the proteolytic release of bradykinin, an endogenous danger signal driving dendritic cell maturation. Scand J Immunol 66: 128-136.
• Schenkman RPF, Vandekerckhove F, Schenkman S 1993. Mammalian cell sialic acid enhances invasion by Trypanosoma cruzi. Infect Immun 61: 898-902.
• Schenkman S, Andrews NW, Nussenzweig V, Robbins ES 1988. Trypanosoma cruzi invade a mammalian epithelial cell in a polarized manner. Cell 55: 157-165.
• Schenkman S, Carvalho LP, Nussenzweig V 1992. Trypanosoma cruzi trans-sialidase and neuraminidase activities can be mediated by the same enzymes. J Exp Med 175: 567-575.
• Schenkman S, Diaz C, Nussenzweig V 1991a. Attachment of Trypanosoma cruzi trypomastigotes to receptors at restricted cell surface domains. Exp Parasitol 72: 76-86.
• Schenkman S, Eichinger D, Pereira MEA, Nussenzweig V 1994. Structural and functional properties of Trypanosoma trans- sialidase. Annu Rev Microbiol 48: 499-523.
• Schenkman S, Ferguson MA, Heise N, de Almeida ML, Mortara RA, Yoshida N 1993. Mucin-like glycoproteins linked to the membrane by glycosylphosphatidylinositol anchor are the major acceptors of sialic acid in a reaction catalyzed by trans-sialidase in metacyclic forms of Trypanosoma cruzi. Mol Biochem Parasitol 59: 293-303.
• Schenkman S, Jiang M-S, Hart GW, Nussenzweig V 1991b. A novel cell surface trans-sialidase of Trypanosoma cruzi generates a stage-specific epitope required for invasion of mammalian cells. Cell 65: 1117-1125.
• Schenkman S, Mortara RA 1992. HeLa cells extend and internalize pseudopodia during active invasion by Trypanosoma cruzi trypomastigotes. J Cell Sci 101: 895-905.
• Schenkman S, Robbins ES, Nussenzweig V 1991c. Attachment of Trypanosoma cruzi to mammalian cells requires parasite energy, and invasion can be independent of the target cell cytoskeleton. Infect Immun 59: 645-654.
• Silva CV, Luquetti AO, Rassi A, Mortara RA 2006. Involvement of Ssp-4-related carbohydrate epitopes in mammalian cell invasion by Trypanosoma cruzi amastigotes. Microbes Infect 8: 2120-2129.
• Silva EO, Saraiva EMB, De Souza W, Souto-Padrón T 1998. Cell surface characterization of amastigotes of Trypanosoma cruzi obtained from different sources. Parasitol Res 84: 257-263.
• Silva JS, Twardzik DR, Reed SG 1991. Regulation of Trypanosoma cruzi infections in vitro and in vivo by transforming growth factor beta (TGF-beta). J Exp Med 174: 539-545.
• Silva LHP, Nussenzweig V 1953. Sobre uma cepa de Trypanosoma cruzi altamente virulenta para o camundongo branco. Folia Clin Biol 20: 191-203.
• Snary D 1985. Receptors and recognition mechanisms of Trypanosoma cruzi. Trans R Soc Trop Med Hyg 79: 587-590.
• Souto RP, Fernandes O, Macedo AM, Campbell DA, Zingales B 1996. DNA markers define two major phylogenetic lineages of Trypanosoma cruzi. Mol Biochem Parasitol 83: 141-152.
• Souto-Padrón T, Almeida IC, De Souza W, Travassos LR 1994. Distribution of alpha-galactosyl-containing epitopes on Trypanosoma cruzi trypomastigote and amastigote forms from infected Vero cells detected by chagasic antibodies. J Eukaryot Microbiol 41: 47-54.
• Stecconi-Silva RB, Andreoli WK, Mortara RA 2003. Parameters affecting cellular invasion and escape from the parasitophorous vacuole by different infective forms of Trypanosoma cruzi. Mem Inst Oswaldo Cruz 98: 953-958.
• Tan H, Andrews NW 2002. Don't bother to knock—the cell invasion strategy of Trypanosoma cruzi. Trends Parasitol 18: 427-428.
• Taniwaki NN, Andreoli WK, Calabrese KS, Silva S, Mortara RA 2005. Disruption of myofibrillar proteins in cardiac muscle of Calomys callosus chronically infected with Trypanosoma cruzi and treated with immunosuppressive agent. Parasitol Res 97: 323-331.
• Taniwaki NN, Machado FS, Massensini AR, Mortara RA 2006. Trypanosoma cruzi disrupts myofibrillar organization and intracellular calcium levels in mouse neonatal cardiomyocytes. Cell Tissue Res 324: 489-496.
• Tanowitz H, Wittner M, Kress Y, Bloom B 1975. Studies of in vitro infection by Trypanosoma cruzi. I. Ultrastructural studies on the invasion of macrophages and L-cells. Am J Trop Med Hyg 24: 25-33.
• Tardieux I, Nathanson MH, Andrews NW 1994. Role in host cell invasion of Trypanosoma cruzi-induced cytosolic-free Ca²⁺ transients. J Exp Med 179: 1017-1022.
• Tardieux I, Webster P, Ravesloot J, Boron W, Lunn JA, Heuser JE, Andrews NW 1992. Lysosome recruitment and fusion are early events required for trypanosome invasion of mammalian cells. Cell 71: 1117-1130.
• Tarleton RL 2007. Immune system recognition of Trypanosoma cruzi. Curr Opin Immunol 19: 430-434.
• Todorov AG, Einicker-Lamas M, De Castro SL, Oliveira MM, Guilherme A 2000. Activation of host cell phosphatidylinositol 3-kinases by Trypanosoma cruzi infection. J Biol Chem 275: 32182-32186.
• Tonelli RR, Silber AM, Almeida-de-Faria M, Hirata IY, Colli W, Alves MJ 2004. L-proline is essential for the intracellular differentiation of Trypanosoma cruzi. Cell Microbiol 6: 733-741.
• Travassos LR, Almeida IC 1993. Carbohydrate immunity in American trypanosomiasis. Springer Semin Immunopathol 15: 183-204.
• Ulrich H, Magdesian MH, Alves MJ, Colli W 2002. In vitro selection of RNA aptamers that bind to cell adhesion receptors of Trypanosoma cruzi and inhibit cell invasion. J Biol Chem 277: 20756-20762.
• Umezawa ES, Milder RV, Abrahamsohn IA 1985. Trypanosoma cruzi amastigotes: development in vitro and infectivity in vivo of the forms isolated from spleen and liver. Acta Trop 42: 25-32.
• Vieira MCF, Carvalho TU, De Souza W 1994. Effect of protein kinase inhibitors on the invasion process of macrophages by Trypanosoma cruzi. Biochem Biophys Res Commun 203: 967-971.
• Villalta F, Kierszenbaum F 1982. Growth of isolated amastigotes of Trypanosoma cruzi in cell-free medium. J Protozool 29: 570-576.
• Villalta F, Kierszenbaum F 1983. Role of cell surface mannose residues in host cell invasion by Trypanosoma cruzi. Biochim Biophys Acta 736: 39-44.
• Villalta F, Kierszenbaum F 1984. Host cell invasion by Trypanosoma cruzi: role of cell surface galactose residues. Biochem Biophys Res Commun 119: 228-235.
• Villalta F, Kierszenbaum F 1985. Role of surface N-acetylglucosamine residues on host cell infection by Trypanosoma cruzi. Biochim Biophys Acta 845: 216-222.
• Villalta F, Lima MF, Howard SA, Zhou L, Ruiz-Ruano A 1992a. Purification of a Trypanosoma cruzi trypomastigote 60- kilodalton surface glycoprotein that primes and activates murine lymphocytes. Infect Immun 60: 3025-3032.
• Villalta F, Lima MF, Ruiz-Ruano A, Zhou L 1992b. Attachment of Trypanosoma cruzi to host cells: a monoclonal antibody recognizes a trypomastigote stage-specific epitope on the gp 83 required for parasite attachment. Biochem Biophys Res Commun 182: 6-13.
• von Kreuter BF, Santos Buch CA 1989. Modulation of Trypanosoma cruzi adhesion to host muscle cell membranes by ligands of muscarinic cholinergic and beta adrenergic receptors. Mol Biochem Parasitol 36: 41-50.
• Wilkowsky SE, Barbieri MA, Stahl P, Isola ELD 2001. Trypanosoma cruzi: phosphatidylinositol 3-Kinase and protein kinase B activation is associated with parasite invasion. Exp Cell Res 264: 211-218
• Wilkowsky SE, Barbieri MA, Stahl PD, Isola ELD 2002. Regulation of Trypanosoma cruzi invasion of nonphagocytic cells by the endocytically active GTPases dynamin, Rab5 and Rab7. Biochem Biophys Res Commun 291: 516-521.
• Wilkowsky SE, Wainszelbaum MJ, Isola ELD 1996. Trypanosoma cruzi: participation of intracellular Ca²⁺ during metacyclic trypomastigote-macrophage interaction. Biochem Biophys Res Commun 222: 386-389.
• Wirth JJ, Kierszenbaum F 1984. Fibronectin enhances macrophage association with invasive forms of Trypanosoma cruzi. J Immunol 133: 460-464.
• Woolsey AM, Sunwoo L, Petersen CA, Brachmann SM, Cantley LC, Burleigh BA 2003. Novel PI 3-kinase-dependent mechanisms of trypanosome invasion and vacuole maturation. J Cell Sci 116: 3611-3622.
• Yoshida N 2002. Trypanosoma cruzi cell invasion mechanisms. In World class parasites. Vol. IV: American trypanosomiasis, KM Tyler, MA Miles (eds.), Kluwer Academic Publishers, Norwell, p. 69-79.
• Yoshida N 2006. Molecular basis of mammalian cell invasion by Trypanosoma cruzi. An Acad Bras Cienc 78: 87-111.
• Yoshida N 2008. Trypanosoma cruzi infection by oral route: how the interplay between parasite and host components modulates infectivity. Parasitol Int 57: 105-109.
• Yoshida N, Blanco SA, Araguth MF, Russo M, Gonzalez JC 1990. The stage-specific 90-kilodalton surface antigen of metacyclic trypomastigotes of Trypanosoma cruzi. Mol Biochem Parasitol 39: 39-46.
• Yoshida N, Cortez M 2008. Trypanosoma cruzi: parasite and host cell signaling during the invasion process. Subcell Biochem 47: 82-91.
• Yoshida N, Dorta ML, Ferreira AT, Oshiro ME, Mortara RA, Acosta-Serrano A, Favoreto JS 1997. Removal of sialic acid from mucin-like surface molecules of Trypanosoma cruzi metacyclic trypomastigotes enhances parasite-host cell interaction. Mol Biochem Parasitol 84: 57-67.
• Yoshida N, Favoreto Jr S, Ferreira AT, Manque PM 2000. Signal transduction induced in Trypanosoma cruzi metacyclic trypomastigotes during the invasion of mammalian cells. Braz J Med Biol Res 33: 269-278.
• Zingales B, Andrews NW, Kuwajima VY, Colli W 1982. Cell surface antigens of Trypanosoma cruzi: possible correlation with the interiorization process in mammalian cells. Mol Biochem Parasitol 6: 111-124.
• Zingales B, Colli W 1985. Trypanosoma cruzi: interaction with host cells. Curr Top Microbiol Immunol 117: 129-152.
• Zwirner NW, Malchiodi EL, Chiaramonte MG, Fossati CA 1994. A lytic monoclonal antibody to Trypanosoma cruzi bloodstream trypomastigotes which recognizes an epitope expressed in tissues affected in Chagas' disease. Infect Immun 62: 2483-2489.

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