Abstract
The close parasite-host relationship involves different aspects such as the biochemical, physiological, morphological, and immunological adaptations. Studies on parasite-host interaction have provided a myriad of information about its biology and have established the building blocks for the development of new drug therapies to control the parasite. Several mechanisms for the parasite invasion have been proposed through in vivo or in vitro experimental data. Since the first histological studies until the studies on the function/structure of the involved molecules, this complex interaction has been roughly depicted. However, new recent strategies as genetic and proteomic approaches have tuned knowledge on how the host reacts to the parasite and how the parasite avoids these host’s reactions in order to survive.
Keywords
- Trypanosoma cruzi
- immune system
- parasite interactions
- animal model studies
- in vitro models
- phagocytic
- non-phagocytic
1. Introduction
The life cycle of
2. An overview of parasite interaction
One of the first barriers faced by
The cellular composition of skin and mucous membranes is a fundamental barrier for permissive or refractory colonization/infection. In the skin, the epidermis is composed by 95% of keratinocytes and other cells present at low concentration, such as melanocytes, Langerhans cells, intra-epithelial lymphocyte, and Merkel cells. Keratinocytes express Toll-like receptors (TLRs) 1–6, 9, and 10 which are able to recognize basically all pathogen-associated molecular patterns (PAMPs) with exception of flagenin; as a consequence, they can secrete an array of mediators such as nitric oxide, leukotrienes, cyclooxygenase, metalloprotease 1 and 9, classical cytokines IL-1, IL-6, IL-8, TNF-alpha, and chemokines CXCL1 and CXCL8. Keratinocytes also express receptors for different cytokines (IL-1, IL-3, TNF-alpha, IL-17, IL-21, IL-22) and chemokines (CXCL9, CXCL10, CXCL11, and CCL20). Other skin cells present at low concentration have also a broad array of receptors that are able to respond to physical and chemical stimulus. In addition, a dense protein layer is found between epidermis and dermis which is composed by collagen type IV, laminin fibronectin, iodogen, and heparan sulfate; together, they structure the basement membrane [10]. The cellular composition of dermis is more complex and diverse. Fibroblast, myofibroblasts, macrophages, adipocytes, dendritic cells, mast cells, and mesenchymal stem cells are found among resident cells in the dermis (Figure 2), whereas transitory cells include lymphocytes, polymorphonuclear cells and monocytes. In addition, dermis presents an intricate network of nerves, lymph, and blood system. As skin, mucosal tissue has the property to react with a complex array of mediators required for immune surveillance and inflammatory response to tissue injury and infection. A remarkable differential feature between skin and mucosa tissue is the bias to immune tolerance and anti-inflammatory response in mucosal compartments [11, 12].
In natural conditions,
3. Specie of vector and Trypanosoma cruzi
Firstly, there are many triatomine vector species that transmit the Chagas disease. Some of them have a wide geographical distribution and others are confined to restricted geographical areas. However, all of them can transmit
The metacyclogenesis of
Once metacyclic trypomastigotes have overcome the first nonspecific immune mechanical barrier (skin/mucosal tissues), they need to swing into the extracellular matrix proteins in order to find cells to invade for replication and then accomplish their life cycle. GP82, a surface glycoprotein found in both bloodstream and tissue-culture trypomastigotes, has the ability to bind to matrix extracellular proteins such as fibronectin, heparan sulfate, and laminin, serving as bridges for parasite-target cell association and leading to enhanced infection. However, this interaction inhibits cell invasion. The presence of the major cysteine proteinase cruzipain (TCC) helps to degrade these extracellular matrix proteins enabling cell invasion [20]. These surface glycoproteins are very polymorphic among
The complement system, another unspecific immune mechanism that is essential for inflammation and cellular lysis, can be activated by three pathways. The lectin triggered by mannose-binding lectins (mannose-binding proteins, ficolins, and CL-K1 proteins) that binds to pathogen-associated molecular pattern (PAMPs) rich in
The four phases of
Finally, it has been observed that in animal models, metacyclic trypomastigotes induce an inflammatory response at the site of inoculation, as early as 1 h, and it is composed basically of neutrophils while mononuclear infiltrate begins at 24 h with a maximum infiltration at day 15. Nonetheless, poor cytokine expression such as IL-2, Il-4, IL-10, IL-12, and IFN-
4. In vitro models
Diverse
Cortez and co-workers [30] recently showed that the participation of lysosomes in the parasite entry site depends on the source of the trypomastigote. They found that the metacyclic trypomastigotes invasion occurs mainly by the lysosome-dependent mechanism, whereas the tissue-culture trypomastigote invasion takes place mostly by the lysosome-independent mechanism. Interestingly, it has been reported that amastigotes are capable of invading host cells by the actin-dependent phagocytic mechanism probably due to their motionless nature [29, 31].
4.1. Lysosomal-dependent
The lysosomal-dependent model is also known as the lysosome exocytosis pathway. Tardieux et al. visualized the recruitment of lysosomes at the parasite entry site during the early event of internalization of tissue-culture trypomastigotes into their mammalian host cells, and they proposed that this process is required for parasite internalization [32]. PGTF is a soluble factor proteolytically generated from trypomastigote which is capable to induce Ca2+ signaling in mammalian cells. The addition of PGTF during the host cell invasion of tissue-culture trypomastigotes showed that Ca2+ signalling plays a role in the parasite invasion through the reorganization of host cell microfilaments as well as in the migration and fusion of lysosomes [15, 33]. In addition, the increase of Ca2+ is required to trigger a form of endocytosis to repair the mechanically injured host cell membrane due to
4.2. Lysosomal-independent
The lysosomal-independent mechanism depends on phosphatidylinositol-3 (PI 3)-kinase (PI3K) which is activated in the presence of
The inhibition of the class I and III PI 3-kinase activities abolishes the parasite entry into macrophages which suggests a prominent role of the host PI 3-kinase activities during the
4.3. Actin-dependent
Amastigotes are also capable to penetrate host cell through its plasma membrane via the actin-dependent mechanism. This mechanism contrasts notably from the two models described previously in which trypomastigotes are involved [41, 42]. The invasion capability of amastigotes depends on the
Once inside the host cell, amastigotes show the same ability as trypomastigotes to disrupt the parasitophorous vacuole, to replicate in the cytosol, and to differentiate into the infective trypomastigote form. There is also evidence that trypomastigotes are able to differentiate into amastigotes extracellularly while circulating in the bloodstream [45]. This remarkable observation has unravelled an additional mechanism through which the parasite can move among intracellular compartments, elude the host immune system, and sustain the infection.
5. Conclusions
Chagas disease is a potentially life-threatening illness caused by
Acknowledgments
The authors acknowledge the National Council of Science and Technology from Mexico (CONACyT). Rosa Lidia Solis-Oviedo was supported by CONACyT. Victor Monteon was financial supported by CONACyT (Project CB-2010-2101 153764). Angel de la Cruz Pech-Canul was supported by CONACyT through the “Cátedras CONACyT para Jóvenes Investigadores” Programme.
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