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Chagas disease, caused by the flagellate protozoan Trypanosma cruzi, is endemic in Central and South Americas where it affects 10 to 12 million people and kills more than 15.000 patients each year. Besides, between 60 and 80 million individuals remain at risk of T. cruzi transmission in endemic countries (OPS. 2006). Furthermore, there are several hundred thousand people infected with T. cruzi in other parts of the world due to migration of Latin Americans towards non-endemic countries, mostly in the USA, Canada, Australia, Japan and Europe. The parasite is transmitted to humans by blood-sucking triatomine bugs (Triatoma, Reduvidae, Hemiptera), by blood or organ transfusion, vertically (in most of the cases congenitally) from the mother to the fetus and, less often, orally by food contamination with live parasites. The annual incidence rate of infection in the endemic zone has been estimated to be 0,008 cases out of 100.000 inhabitants by the Pan American Health Organization (PAHO), with 41.200 cases of vectorial transmission and 14.385 cases of congenital transmission yearly (OPS. 2006, Pinto Dias et al. 2010)
Developmental cycle and parasitological form
T. cruzi is a flagellate of the order Kinetoplastidae, family Trypanosomatidae, characterized by the presence of one flagellum and a single mitochondrion which contains a specialized DNA-containing organelle named kinetoplast. During its dixene cycle, the parasite undergoes four distinct morphological and physiological evolutionary stages, which are identified by the relative position of the kinetoplast and the flagellum regarding to the cell nucleus (De Souza, 2002 - autre?): The trypomastigote is the extracellular elongated form found in the vertebrate host, classically known as infective form, which disseminate throughout the host body. Its kinetoplast is situated posteriorly in relation to the nucleus located in the middle of the parasite and presents a large free flagellum originating near the kinetoplast. The amastigote is the intracellular spherical stage in vertebrate cells, which multiplies by longitudinal binary fission. It displays a short discreet flagellum and the kinetoplast is near the nucleus. The spheromastigote is the spherical form found in the midgut of the bug, quite similar to amastigote but with a bigger flagella, which is the transition between the blood and vector elongated forms. Finally, the epimastigote is the extracellular elongated form present in the intestinal tract and urine of the insect vector, where it also multiplies by longitudinal binary fission. Its kinetoplast and the free flagellum are located in the anterior position of the nucleus (Tyler et al. 2001, de Lana et al. 2010).
Infection of the vertebrate host is perfomed by metacyclic trypomastigotes, present in the excreta of a bug, which enter through the insect bite wound or mucosal tissues. The metacyclic form is able to invade a wide range of phagocytic and nonphagocytic nucleated cells. Invasion occurs by one of three distinct mechanisms after interaction parasite-host cell (favored by several molecules like gp82 glycoprotein or sialic acid Alves and Mortara, 2009 ?). The best-studied of them is lysosome dependent: T. cruzi organizes the microtubule cytoskeleton of the host cell in order to direct recruit lysosomes to the point of parasite attachment. These lysosomes then fuse with the plasma membrane, first forming a junction with the parasite and then creating a vacuolar compartment, called the parasitophorous vacuole, in which the entering parasite transiently resides. Invasion may also be facilitated by the host actin cytoskeleton: the parasitophorous vacuole is initially constructed from the plasma membrane of the host cell, which distorts in pseudopodes along the parasite and includes it. Finally, it has been proved that the parasite may enter a cell under pressure from its own motility (ref). Nevertheless, this mechanism is thought to be the least important mechanism of invasion. Once within the vacuole by any of these mechanisms, lysosomes continue to traffic to and fuse with the parasitophorous vacuole, leading to its acidification. This induces the rapid differentiation to an amastigote and activates a parasite derived porin, Tc-tox, that destroys the vacuole membrane, permitting the escape of the parasite into the cytoplasm where the amastigote proliferates by binary fission. When the cell is filled with these forms, the amastigotes elongate, reacquiring their long flagella and differentiate into trypomastigotes. When the cell becomes filled with these former, the plasma membrane ruptures and significant degenerative processes can be observed, probably due to the intense movement of the parasites (Alves and Mortara, 2009). Trypomastigotes that are released outside the cell can invade adjacent cells or enter the blood and lymph circulation and disseminate. It is important to note that amastigotes are also infective and can be found in the blood. Both forms can be taken up in the blood meal of a bug, going to their midgut where they differentiate into amastigotes that extend their flagella to become spheromastigotes, which further lengthen to become epimastigotes. These forms, that are also able to replicate, migrate to the insect rectum where they attach by their flagella and undergo metacyclogenesis to human infective trypomastigote forms which, once totally transformed, are excreted with the excreta, completing the life cycle. (Tyler et al. 2003 + 2001 à voir, de Lana et al. 2010)
Due to their lack of sexual reproduction, T. cruzi is not evolving like other eukaryotic species. Indeed, the multiplication by binary fission described above lead to apparition of homogeneous lineages isolated from each other. Six major lineages or DTUs (discrete typing units which can be defined as sets of stocks that are genetically closer to each other than to any other stock) are identifiable by common molecular, genetic, biochemical, or immunological markers (Tibayrenc et al. 2010). These major lineages named T. cruzi I, IV, II, III, V and VI (corresponding to the previous I, IIb, IIc, IIa, IId and IIe respectively) are not homogeneously distributed in Latin America and have preferential hosts. However, we can find all lineages in humans of all geographic part. Many studies have been done in order to know if some lineages were more infectious or lead to more complications than others but, for now, even if there are many instances of local associations between parasite genetics and clinical outcome, no global correlations have been clearly demonstrated. (Tibayrenc et al. 2010, Macedo et al. 2010)
Clinic aspects, diagnostic and treatment
Chagas disease has two successive phases, acute and chronic. The acute phase, in which the general mortality rate in nontreated individuals ranges from 2% to 12%, lasts 6 to 8 week. Most of the infected patients recover an apparent healthy status, entering in the indeterminate chronic form, where no organ damage can be demonstrated by the current standard methods of clinical diagnosis. While most patients remain in this form of the disease, 20 to 35% of the infected individuals will develop irreversible lesions of the autonomous nervous system in the heart (represents the first cause of cardiac lesions in young adults in the endemic countries in Latin America), esophagus, colon, and peripheral nervous system after several years of the chronic phase (Moncayo et al. 2010). This chronic phase now constitutes the major problem in endemic and nonendemic countries. Indeed, at least 20% of the millions of Chagasic patients will develop chronic heart or digestive disease. All of these people are potential transmitters of the parasite by means of blood and organ transplantation, and those patients suffering Chagas heart disease certainly will have severe working limitations, high costs concerning medical attention, and reduced life expectancy (Pinto Dias et al. 2010).
The diagnostic necessities have changed with the globalization of the infection by T. cruzi in non-endemic countries. Taking into account that the vast majority of infected individuals are at the chronic asymptomatic phase, their only marker would be the presence of T. cruzi antibodies, with the possibilitythat the infected individuals have no complaints or clinical abnormalities. The suspicion may thus also come from the epidemiological background of the patient (past residence in endemic areas, family history or work with the parasite). Laboratory diagnosis includes parasitological and serological tests, depending on the suspected phase of the disease: parasitological tests during the acute phase or serological ones during the chronic phase. The frequently used direct parasitological is the fresh blood smear (more sensitive than a dry smear or a thick smear). If no parasite is found, concentration techniques based on centrifugation as microhaematocrit or Strout technique are preferentially used but xenodiagnoses or hemoculture may also been practiced, overall for chronic disease diagnostic. Finally, PCR is a quite new diagnostic tool but its specificity is not always assured. Many different serological tests (indirect hemagglutination test, indirect immunofluorescence, ELISA â€¦) have been designed and the WHO recommends employing at least two tests in parallel to insure the diagnosis.
There are actually two drugs on the market employed to cure Chagas disease: Nifurtimox and Benznidazole which act by the production of free radicals, superoxide anions, hydrogen peroxide and electrophilic metabolites (Apt et al. 2000). If these drugs bring concrete benefits for acute cases and young chronic, studies have established that the treatment is only effective for a minor proportion (20%) of chronic older individuals (Pinto Dias et al. 2010, Apt et al. 2010). Other drugs are currently under studies but the lack of biological markers of cure for chronic disease (serology remains sometimes positive till 20 years after effective treatment and absence of parasite in blood doesn't mean absence of parasites in tissues) makes tough their development. Importantly, since the people with Chagas disease have generally low economic resources, big pharmaceutical companies are not interested to develop new drugs for this disease and the production of Nifurtimox and Benznidazole have even been stopped by their respective firms, letting uniquely a Brazilian laboratory produce Benznidazole which to date have not the capacities to meet the global drug need (Apt et al. 2000).
Congenital disease is due to a maternal-fetal transmission of T. cruzi live parasites that took place in utero (prenatal transmission) or at the time of delivery (perinatal transmission) that persist after birth. It thus excludes the "postnatal" transmission of parasites (mainly through maternal milk by breast-feeding) and the transmission of dead parasites or parasite DNA. Even if congenital T. cruzi infection is an acute infection, most of cases are asymptomatic (ref). However, non-specific clinical manifestations like fever, low birth weight (less than 2500 g), prematurity, hepato-splenomegaly, pneumonitis and, more rarely, jaundice can occur (ref).
The transmission rate, defined as the ratio between the number of congenital cases and the number of infected mothers, is described to be between 1% and 12%, depending of the geographic regions and the diagnostic test used (Carlier and Torrico, 2003). In contrast to other congenital transmission like toxoplasmosis or CMV, transmission of T. cruzi can occur in both acute and chronic phases of maternal infection and thus be repeated at each pregnancy (Carlier and Torrico, 2003) during all of the fertile period of a woman's life (Carlier and Torrico, 2003). This matter of fact induces that, even if other transmission ways are eradicated, transgenerational transmission of parasites can persist during several other decades in endemic as well as in nonendemic areas. This highlights that congenital infection with T. cruzi as an important public health problem that can easily extend in space (through migrations) and time (Carlier and Torrico, 2003).
The congenital transmission is described to be mostly transplacental, infecting trophoblastic layers or other placental tissues like marginal zone, mesenchymal tissues and finally reaching fetal vessels embedded in such tissue. Studies have also pointed the possibility of an infection through parasites released into amniotic fluid contaminating fetuses by oral or pulmonary routes but antimicrobial peptides normally contained in amniotic fluid (Akinbi et al., 2004) make this atypical. (Carlier et al. 2010)
The main factors that permit occurrence and development of a congenital infection are the parasite itself, the mother and the fetal capacity to respond to parasite invasion. Up to date, there is no relationship between T. cruzi lineages (Â§2.7.2) and congenital infection in humans (Virreira et al. 2006). Besides, since 53% of pregnant women displaying high parasitemia transmitted the parasite for only 1-12% of chronically infected women in which blood parasites are hardly detectable (ref? 22.2.1 to see - ask YC) and the rate of hemoculture positive is twofold higher in chronically infected mothers transmitting parasites than in untransmitting ones (Hermann et al. 2004), parasitemia in pregnant women seems to be an important factor contributing to congenital transmission of T. cruzi (Carlier et al. 2010). Quite related to this, it has been proved that a tinier IFN-ï§ production by T cells of the mother correlate with a higher risk of parasite transmission to their fetus, certainly due to a higher parasitemia (Hermann et al. 2004). In general, a good immune response from the mother against the parasite (Â§ 2.8) permit a decrease in the risk of transmission. Other maternal factors such as young age and/or primiparity, and/or malnutrition and poverty also favor the congenital transmission of T. cruzi (ref). Finally, the fetus itself can contribute to stop the congenital infection. Indeed, it has been shown that uninfected neonates born to infected mothers produce inflammatory cytokines at a higher rate than infected ones (Vekemans et al. 2000) and it is thought that parasite, opsonized by transferred maternal antibodies, can be eliminated by their activated monocytes (Â§ 2.8.3) (Carlier et al. 2010).
Since a child born with congenital Chagas disease, whatever the neonatal morbidity, is at risk to develop into chronic determinate disease in ageing and the treatment of very young infants with Benznidazole and Nifurtimox is very effective (90 - 100% of cure, Apt et al. 2010, Carlier et Torrico 2003), it is of the highest importance to detect the infection. In order to perform this, a systematic screening of the mothers has to be effected serologically and, if this test is positive, research of live trypomastigotes at birth and of specific-antibodies after 8 months of age have to be performed.
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