Navegando por Autor "Guedes, Paulo Marcos da Matta"

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Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts.
(2004) Guedes, Paulo Marcos da Matta; Urbina, Julio Alberto; Lana, Marta de; Afonso, Luís Carlos Crocco; Veloso, Vanja Maria; Tafuri, Washington Luiz; Coelho, George Luiz Lins Machado; Chiari, Egler; Bahia, Maria Terezinha
Albaconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in dogs, monkeys, and humans. In the present work, we investigated the in vivo activity of this compound against two strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas’ disease, using dogs as hosts. The T. cruzi strains used in the study were previously characterized (murine model) as susceptible (strain Berenice-78) and partially resistant (strain Y) to the drugs currently in clinical use, nifurtimox and benznidazole. Our results demonstrated that albaconazole is very effective in suppressing the proliferation of the parasite and preventing the death of infected animals. Furthermore, the parasitological, PCR, serological, and proliferative assay results indicated parasitological cure indices of 25 and 100% among animals inoculated with T. cruzi strain Y when they were treated with albaconazole at 1.5 mg/kg of body weight/day for 60 and 90 days, respectively. On the other hand, although albaconazole given at 1.5 mg/kg/day was very effective in suppressing the proliferation of the parasite in animals infected with the Berenice-78 T. cruzi strain, no parasitological cure was observed among them, even when a longer treatment period (150 doses) was used. In conclusion, our results demonstrate that albaconazole has trypanocidal activity in vivo and is capable of inducing radical parasitological cure, although natural resistance to this compound was also indicated. Furthermore, the compound can be used in long-term treatment schemes (60 to 150 days) with minimal toxicity and thus represents a potentially useful candidate for the treatment of human Chagas’ disease.
Advances in Chagas disease chemotherapy.
(2006) Guedes, Paulo Marcos da Matta; Fietto, Juliana Lopes Rangel; Lana, Marta de; Bahia, Maria Terezinha
Chagas disease is endemic from Mexico to Argentina, where it is estimated that 16 to 18 million people are infected with its causative agent, Trypanosoma cruzi, and 100 million remain at risk of infection, emphasizing the necessity to sustain and extend control measures and strategies to combat this disease. Specific chemotherapy with benznidazole or nifurtimox has been recommended for treatment of recent and congenital infection. However, clinical trials with nifurtimox and benznidazole have shown that these compounds have very low activity in preventing the development of chronic Chagas disease. Moreover, the drugs induce a number of toxic side effects. The discovery of new active, non-toxic compounds would probably expand treatment, including those patients in which clinical manifestations are absent or can only be disclosed by more elaborate medical procedures. Recent developments in the study of basic biochemical aspects of T. cruzi have allowed for the identification of new targets for chemotherapy. Like many fungi, T. cruzi has a strict requirement for specific endogenous sterol synthesis for cell viability and growth and is extremely susceptible to sterol biosynthesis inhibitors (SBI). An intensive investigation of the potential trypanocidal effect of specific SBI has been performed, and it was demonstrated that some of these compounds exhibited suppressive and curative activity in murine and dog models of acute and chronic Chagas disease. Other potential targets for anti-T. cruzi chemotherapy that include the antiproliferative lysophospholipid analogs (evaluated in clinical trials as the first oral treatment for visceral leishmaniasis), cysteine protease inhibitors and compounds that interfere with purine salvage and inositol metabolism are also discussed.
Avaliação da terapia com células tronco mesenquimais da medula óssea na cardiopatia chagásica de cães infectados por Trypanosoma cruzi.
(2019) Nascimento, Alvaro Fernando da Silva do; Bahia, Maria Terezinha; Carvalho, Adriana Bastos; Bahia, Maria Terezinha; Roatt, Bruno Mendes; Guedes, Paulo Marcos da Matta; Santos, Silvana Maria Elói; Lima, Wanderson Geraldo de
Neste estudo foi avaliada a eficácia das células-tronco mesenquimais (MSCS) de medula óssea, isoladamente ou em combinação com a terapia convencional para insuficiência cardíaca, no tratamento da cardiopatia chagásica crônica. Cães infectados com a cepa VL-10 de Trypanosoma cruzi foram tratados com MSCs de origem autóloga ou alogeneicas. Os animais receberam, em dose única, por via intravenosa, 5 milhões de células/kg entre 6 a 8 meses após a infecção. Adicionalmente, outros grupos de animais receberam o tratamento farmacológico (enalapril 5mg e carvedilol 3,125mg) associado ou não à terapia celular. A avaliação da função cardíaca foi realizada através de ecocardiografias seriadas (antes e 45, 90 e 180 dias após o tratamento). O efeito da terapia celular na intensidade das lesões teciduais foi avaliado por análise quantitativa de miocardite e fibrose no tecido muscular cardíaco (câmaras cardíacas, ápice e septo interventricular) dos animais necropsiados 6-8 meses após os tratamentos. A função sistólica, avaliada pela fração de ejeção, não apresentou diferença significativa entre os animais dos diversos grupos experimentais ao longo do período avaliado. No entanto, a comparação dos valores de FEVE obtidos antes e seis meses após o tratamento mostra diferentes padrões de evolução da função sistólica entre os animais dos diversos grupos experimentais. Os animais não infectados mantiveram a FEVE acima de 40% durante o período de avaliação. Os animais dos grupos MSCAUT, MSCAUT+TF e TF não apresentaram alterações acentuadas na função sistólica no período de acompanhamento. Por outro lado, entre os animais do grupo MSCALO foi observada a redução da percentagem de animais com disfunção sistólica (55% para 22%). Em contraste, um aumento da percentagem de animais com disfunção sistólica (30% para 60%) foi detectado entre animais infectados e não tratados. Além disso, se apenas animais com disfunção sistólica no período prétratamento forem considerados, uma melhora significativa na função sistólica dos animais tratados com MCSALO, em relação aos animais infectados e não tratados, pode ser observada. Em concordância, o tratamento com MSCs foi capaz de reduzir significativamente a miocardite e a fibrose na maioria das regiões cardíacas avaliadas. Além disso, foi observada a redução da apoptose e o aumento da mitose no átrio direito dos animais tratados com MSCS em relação aos animais infectados e não tratados. Diferentemente, o tratamento farmacológico foi capaz induzir a redução da apoptose, mas não de aumentar a mitose no átrio direito dos animais. Em seguida, foi avaliada a expressão dos fatores de transcrição associados às linhagens de células T efetoras Th1 e Th2. Os resultados desta avaliação mostraram que a infecção por T. cruzi induziu uma expressão aumentada de mRNA dos marcadores de resposta Th1 e Th2 no átrio direito de animais. O perfil de resposta imune induzido pela infecção por T. cruzi não foi alterado pelo tratamento com MSCAUT, MSCAUT+TF ou TF. Por outro lado, expressões reduzidas de mRNA para T-bet, IFN-γ, TNFα, CCL5 / CCR5 e expressão aumentada de mRNA para IL-10 foram detectadas no tecido (átrio direito) dos animais tratados com MSCALO. Em geral, os resultados deste estudo mostraram o efeito benéfico do tratamento da cardiopatia chagásica com MSCs, especialmente com MSCS de origem alogeneica. Entretanto, novos estudos, utilizando um maior número de animais com disfunção sistólica no momento do tratamento, devem ser realizados para confirmar o por T. cruzi.
Benznidazole therapy during acute phase of chagas disease reduces parasite load but does not prevent chronic cardiac lesions.
(2008) Caldas, Ivo Santana; Silva, André Talvani Pedrosa da; Caldas, Sérgio; Carneiro, Cláudia Martins; Lana, Marta de; Guedes, Paulo Marcos da Matta; Bahia, Maria Terezinha
The goals of this study were to evaluate the efficacy of benznidazole (Bz) treatment in decreasing of the parasitic load during the acute phase of experimental Chagas disease and to analyze its influence in the development of cardiac chronic alterations in mice inoculated with drug-resistant Trypanosoma cruzi strains. Our results showed that the early Bz treatment (started at 4th day of infection) was efficient in reducing the parasite load in animals from both acute and chronic phase of the infection. Moreover, this reduction in the parasite load could not be associated with the intensity of the cardiac chronic lesions. The histopathological evaluation of cardiac tissue of Bz-treated mice showed three different patterns of response: (1) presence of a small number of inflammatory cells and fibrotic area similar to noninfected mice; (2) similar intensity of inflammatory infiltrate and smaller fibrotic area in relation to nontreated animals; (3) similar intensity of inflammatory infiltrated and fibrosis area among the Bz-treated and nontreated animals. Each specific pattern was obtained with different T. cruzi strain, suggesting that the pattern of the heart lesions in chronic phase of Bz-treated animals was T. cruzi strain dependent but not related with drug resistance levels.
Development of chronic cardiomyopathy in canine Chagas disease correlates with high IFN-g, TNF-a, and low IL-10 production during the acute infection phase.
(2009) Guedes, Paulo Marcos da Matta; Veloso, Vanja Maria; Afonso, Luís Carlos Crocco; Caliari, Marcelo Vidigal; Carneiro, Cláudia Martins; Diniz, Lívia de Figueiredo; Silva, Eduardo de Almeida Marques da; Caldas, Ivo Santana; Matta, Maria Adelaide do Valle; Souza, Sheler Martins de; Lana, Marta de; Chiari, Egler; Galvão, Lúcia Maria da Cunha; Bahia, Maria Terezinha
When infected with Trypanosoma cruzi, Beagle dogs develop symptoms similar to those of Chagas disease in human beings, and could be an important experimental model for a better understanding of the immunopathogenic mechanisms involved in chronic chagasic infection. This study evaluates IL-10, IFN-g and TNF-a production in the sera, culture supernatant, heart and cervical lymph nodes and their correlation with cardiomegaly, cardiac inflammation and fibrosis in Beagle dogs infected with T. cruzi. Pathological analysis showed severe splenomegaly, lymphadenopathy and myocarditis in all infected dogs during the acute phase of the disease, with cardiomegaly, inflammation and fibrosis observed in 83% of the animals infected by T. cruzi during the chronic phase. The data indicate that infected animals producing IL-10 in the heart during the chronic phase and showing high IL-10 production in the culture supernatant and serum during the acute phase had lower cardiac alterations (myocarditis, fibrosis and cardiomegaly) than those with high IFN-g and TNF-a levels. These animals produced low IL-10 levels in the culture supernatant and serum during the acute phase and did not produce IL-10 in the heart during the chronic phase of the disease. Our findings showed that Beagle dogs are a good model for studying the immunopathogenic mechanism of Chagas disease, since they reproduce the clinical and immunological findings described in chagasic patients. The data suggest that the development of the chronic cardiac form of the disease is related to a strong Th1 response during the acute phase of the disease, while the development of the indeterminate form results from a blend of Th1 and Th2 responses soon after infection, suggesting that the acute phase immune response is important for the genesis of chronic cardiac lesions.
Effects of ravuconazole treatment on parasite load and immune response in dogs experimentally infected with trypanosoma cruzi.
(2010) Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Guedes, Paulo Marcos da Matta; Crepalde, Geovam Pereira; Lana, Marta de; Carneiro, Cláudia Martins; Silva, André Talvani Pedrosa da; Urbina, Julio Alberto; Bahia, Maria Terezinha
In this work, we investigated the in vivo activity of ravuconazole against the Y and Berenice-78 Trypanosoma cruzi strains using acutely infected dogs as hosts. Ravuconazole was well tolerated, as no significant side effects were observed during the treatment using 6.0 mg/kg twice a day (12 mg/kg/day) for up to 90 days. In all treated animals, parasitemia was permanently suppressed by the first day of treatment, independently of the parasite strain. Cultures of blood obtained posttreatment were negative for 90% of the animals, confirming that the drug induced a marked reduction in the parasite load. The results of PCR tests for T. cruzi in blood performed 1 month posttreatment were consistently negative for three of five and two of five animals infected with the Y and Berenice-78 strains, respectively. All ravuconazole-treated dogs consistently had negative serological test results during and until 30 days after treatment, regardless of the therapeutic scheme used. However, after the end of treatment, an increase in specific antibody levels was observed in all treated animals, although the antibody levels were always significantly lower than those of the nontreated control dogs. Despite being unable to induce a parasitological cure, ravuconazole treatment led to significant reductions in the levels of gamma interferon expression and lesions in cardiac tissues in animals infected with the Y strain, while the level of interleukin-10 mRNA expression increased. We conclude that ravuconazole has potent suppressive but not curative activity in the canine model of acute Chagas' disease, probably due to its unfavorable pharmacokinetic properties (half-life, 8.8 h). The longer half-life of ravuconazole in humans (4 to 8 days) makes it a promising drug for assessment for use as chemotherapy in human Chagas' disease.
Genetic modulation in Be-78 and Y Trypanosoma cruzi strains after long-term infection in Beagle dogs revealed by molecular markers.
(2012) Veloso, Vanja Maria; Guedes, Paulo Marcos da Matta; Lana, Marta de; Martins, Helen Rodrigues; Carneiro, Cláudia Martins; Câmara, Antônia Cláudia Jácome da; D’Ávila, Daniella Alchaar; Caldas, Ivo Santana; Galvão, Lúcia Maria da Cunha; Chiari, Egler; Bahia, Maria Terezinha
The genetic profile of Trypanosoma cruzi was evaluated in parasite populations isolated from Beagle dogs experimentally infected with Be-78 and Y strains that present distinct biological and genetic characteristics. Molecular characterization of the isolates obtained 30 days and 2 years after infection was carried out. For typing MLEE, sequence polymorphisms of the mitochondrial cytochrome oxidase subunit II gene (COII) and RAPD profiles were used. The profiles of MLEE were the same for the parental Be-78 strains as their respective isolates. However, changes of MLEE profile were observed in two T. cruzi isolates from dogs inoculated with Y strain. Changes in the mitochondrial DNA (COII) and RAPD profiles of the Y strain were also observed. The dendogram constructed by UPGMA with RAPD results indicated two major branches. Global data show that the genetic modulation in polyclonal strains during the long-term infection occurred and was strain-dependent. This study still suggests that each host (here each dog) harbors a determinate T. cruzi population that may change or be modulated throughout long-term infection. This might to hinder the observation of correlation between the genetics of T. cruzi and their biological properties and behavior in different host species due to the complexity of the parasite-host interaction in which probably the genetic background of both should be considered.
Hematological alterations during experimental canine infection by Trypanosoma cruzi.
(2012) Guedes, Paulo Marcos da Matta; Veloso, Vanja Maria; Mineo, Tiago Wilson Patriarca; Silva, Juliana Santiago; Crepalde, Geovam Pereira; Caldas, Ivo Santana; Nascimento, Manuela Sales Lima; Lana, Marta de; Chiari, Egler; Galvão, Lúcia Maria da Cunha; Bahia, Maria Terezinha
Para confirmar que cães Beagle são um bom modelo para doença de Chagas, foram avaliadas as alterações hematológicas durante as fases aguda e crônica em cães Beagle infectados com as cepas Y, Berenice-78 (Be-78) e ABC de Trypanosoma cruzi, correlacionando os sinais clínicos com a curva de parasitemia. Foi demonstrado que a fase aguda da infecção foi marcada por letargia e perda de apetite. Simultaneamente, observou-se anemia, leucocitose e linfocitose. Ainda, foram descritas alterações hematológicas e sinais clínicos positivamente correlacionados com a parasitemia durante a infecção experimental com as três cepas de T. cruzi estudadas, demonstrando que a infecção em cães Beagle constitui um modelo fidedigno para a doença de Chagas.
IgG isotype profile is correlated with cardiomegaly in Beagle dogs infected with distinct Trypanosoma cruzi strains.
(2008) Guedes, Paulo Marcos da Matta; Veloso, Vanja Maria; Gollob, Kenneth John; Afonso, Luís Carlos Crocco; Caldas, Ivo Santana; Vianna, Priscila; Lana, Marta de; Chiari, Egler; Bahia, Maria Terezinha; Galvão, Lúcia Maria da Cunha
A systematic study following infection by various strains of the protozoan parasite, Trypanosoma cruzi, and the simultaneous monitoring of the humoral immune response together with the elicited cellular response, could add greatly to our understanding of differences between strains of this important human pathogen. In that sense, acute and chronic infections with distinct T. cruzi strains (Y, Berenice-78 and ABC) in Beagle dogs were studied through a longitudinal evaluation of immunoglobulin G (IgG), IgG1 and IgG2 isotypes (by ELISA and flow cytometry (FC)), as well as measurements of peripheral blood mononuclear cell (PBMC) proliferation over a 100-week period, and their correlation with cardiomegaly. Our results show that infected animals presenting cardiomegaly showed lower or absent levels of IgG1 during the chronic phase of the infection, when compared to those that did not show an increase in heart weight. In that manner, our results suggest that IgG1 could be used as a marker for cardiac pathogenicity in Chagas disease.
Increased type 1 chemokine expression in experimental Chagas disease correlates with cardiac pathology in Beagle dogs.
(2010) Guedes, Paulo Marcos da Matta; Veloso, Vanja Maria; Silva, André Talvani Pedrosa da; Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Matta, Maria Adelaide do Valle; Silva, Juliana Santiago; Chiari, Egler; Galvão, Lúcia Maria da Cunha; Silva, João Santana da; Bahia, Maria Terezinha
Chemokines and chemokine receptors interaction have presented important role in leukocyte migration to specific immune reaction sites. Recently, it has been reported that chemokine receptors CXC (CXCR3) and CC (CCR5) were preferentially expressed on Th1 cells while CCR3 and CCR4 were preferentially expressed on Th2 cells. This study evaluated the mRNA expression of type 1 and type 2 chemokine and chemokine receptors in the cardiac tissue of Beagle dogs infected with distinct genetic groups of Trypanosoma cruzi (Y, Berenice- 78 and ABC strains) during acute and chronic phases. To analyze the correlation between chemokine and chemokine receptors expression and the development of heart pathology, the chronic infected animals were divided into groups, according to the parasite strain and based on the degree of heart damage: cardiac and indeterminate form of Chagas disease. Our results indicated that cardiac type1/2 chemokines and their receptors were partially dependent on the genetic diversity of parasites as well as the polarization of clinical forms. Also, dogs presenting cardiac form showed lower heart tissue mRNA expression of CCL24 (type 2) and higher expression of CCL5, CCL4 and CXCR3 (type 1) when compared with those with indeterminate form of disease. Together, these data reinforce a close-relation between T. cruzi genetic population and the host specific type 1 immune response and, for the first time, we show the distribution of type 1/2 chemokines associated with the development of cardiac pathology using dogs, a well similar model to study human Chagas disease.
Inflammation enhances the risks of stroke and death in chronic chagas disease patients.
(2016) Guedes, Paulo Marcos da Matta; Andrade, Cléber Mesquita de; Nunes, Daniela Ferreira; Pereira, Nathalie de Sena; Queiroga, Tamyres Bernadete Dantas; Coelho, George Luiz Lins Machado; Nascimento, Manuela Sales Lima; Matta, Maria Adelaide do Valle; Câmara, Antônia Cláudia Jácome da; Chiari, Egler; Galvão, Lúcia Maria da Cunha
Ischemic strokes have been implicated as a cause of death in Chagas disease patients. Inflammation has been recognized as a key component in all ischemic processes, including the intravascular events triggered by vessel interruption, brain damage and repair. In this study, we evaluated the association between inflammatory markers and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. The mRNA expression levels of cytokines, transcription factors expressed in the adaptive immune response (Th1, Th2, Th9, Th17, Th22 and regulatory T cell), and iNOS were analyzed by realtime PCR in peripheral blood mononuclear cells of chagasic patients who exhibited the indeterminate, cardiac, digestive and cardiodigestive clinical forms of the disease, and the levels of these transcripts were correlated with the DR and SR. Cardiac patients exhibited lowermRNA nexpression levels of GATA-3, FoxP3, AHR, IL-4, IL-9, IL-10 and IL 22 but exhibited higher expression of IFN-γ and TNF-α compared with indeterminate patients. Digestive patients showed similar levels of GATA-3, IL-4 and IL-10 than indeterminate patients. Cardiodigestive patients exhibited higher levels of TNF-α compared with indeterminate and digestive patients. Furthermore, we demonstrated that patients with high DR and SR exhibited lower GATA-3, FoxP3, and IL-10 expression and higher IFN-γ, TNF-α and iNOS mRNA expression than patients with low DR and SR. A negative correlation was observed between Foxp3 and IL-10 mRNA expression and the DR and SR. Moreover, TNF-α and iNOS expression was positively correlated with DR and SR. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is associated with a high DR and SR. This study provides a better understanding of the stroke pathobiology in the general population and might aid the development of therapeutic strategies for controlling the morbidity and mortality of Chagas disease.
Influence of ecto-nucleoside triphosphate diphosphohydrolase activity on Trypanosoma cruzi infectivity and virulence.
(2009) Santos, Ramon de Freitas; Pôssa, Marcela Auxiliadora Souza; Bastos, Matheus Silva e; Guedes, Paulo Marcos da Matta; Almeida, Márcia Rogéria de; DeMarco, Ricardo; Almeida, Sergio Verjovski; Bahia, Maria Terezinha; Fietto, Juliana Lopes Rangel
Background: The protozoan Trypanosoma cruzi is the causative agent of Chagas disease. There are no vaccines or effective treatment, especially in the chronic phase when most patients are diagnosed. There is a clear necessity to develop new drugs and strategies for the control and treatment of Chagas disease. Recent papers have suggested the ecto-nucleotidases (from CD39 family) from pathogenic agents as important virulence factors. In this study we evaluated the influence of Ecto- Nucleoside-Triphosphate-Diphosphohydrolase (Ecto-NTPDase) activity on infectivity and virulence of T. cruzi using both in vivo and in vitro models. Methodology/Principal Findings: We followed Ecto-NTPDase activities of Y strain infective forms (trypomastigotes) obtained during sequential sub-cultivation in mammalian cells. ATPase/ADPase activity ratios of cell-derived trypomastigotes decreased 3- to 6-fold and infectivity was substantially reduced during sequential sub-cultivation. Surprisingly, at third to fourth passages most of the cell-derived trypomastigotes could not penetrate mammalian cells and had differentiated into amastigote-like parasites that exhibited 3- to 4-fold lower levels of Ecto-NTPDase activities. To evidence the participation of T. cruzi Ecto-NTPDase1 in the infective process, we evaluated the effect of known Ecto- ATPDase inhibitors (ARL 67156, Gadolinium and Suramin), or anti-NTPDase-1 polyclonal antiserum on ATPase and ADPase hydrolytic activities in recombinant T. cruzi NTPDase-1 and in live trypomastigotes. All tests showed a partial inhibition of Ecto-ATPDase activities and a marked inhibition of trypomastigotes infectivity. Mice infections with Ecto-NTPDase-inhibited trypomastigotes produced lower levels of parasitemia and higher host survival than with non-inhibited control parasites. Conclusions/Significance: Our results suggest that Ecto-ATPDases act as facilitators of infection and virulence in vitro and in vivo and emerge as target candidates in chemotherapy of Chagas disease.
Influência do tratamento com benznidazol na resposta imune celular e na miocardite de cães infectados por Trypanosoma cruzi.
(2014) Nascimento, Alvaro Fernando da Silva do; Bahia, Maria Terezinha; Bahia, Maria Terezinha; Guedes, Paulo Marcos da Matta; Bezerra, Frank Silva
A cardiopatia chagásica crônica (CCC) afeta aproximadamente 30% dos 8 milhões de indivíduos infectados pelo Trypanosoma cruzi. Mesmo considerando que o infiltrado inflamatório, rico em células Th1, desempenha um papel crucial na CCC, pouco se sabe sobre os fatores que controlam a migração de células inflamatórias para o miocárdio na CCC. Neste estudo foi analisada a expressão do mRNA para citocinas, quimiocinas/receptores e fatores de transcrição relacionados às respostas tipo Th1 e Th2 presentes no tecido muscular cardíaco de cães infectados pelas cepas Berenice-78 (susceptível ao benznidazol) e VL-10 (resistente ao benznidazol) durante as fases aguda e crônica da infecção. Para analisar a influência do tratamento com benznidazol no padrão de resposta imune os animais foram divididos nos seguintes grupos experimentais: (i) animais infectados, (ii) animais tratados e curados, (iii) animais tratados e não curados, (iv) animais não infectados. Nossos resultados mostraram que durante a fase aguda da infecção pelo T. cruzi foi observada uma intensa inflamação do tecido muscular cardíaco associada a uma resposta tipo-Th1 predominante. A evolução para a fase crônica da doença conduziu a uma redução significativa da inflamação, pois nesta fase foi detectado um número significativamente menor de núcleos celulares em relação à fase aguda (p<0,05) tanto nos animais infectados pela cepa VL-10 (301,26±30,69 núcleos celulares na fase aguda e 243,78±20,56 na fase crônica), quanto naqueles infectados pela cepa Berenice-78 (277,45±55,44 núcleos celulares na fase aguda e 198,65±15,46 na fase crônica). A redução do processo inflamatório foi associado com a redução na detecção de mRNA para fatores de transcrição, quimiocinas/receptores relacionados às respostas Th1, Th2 e Th17. Adicionalmente foi demonstrado que o tratamento específico induz, no caso de cura parasitológica, uma redução da inflamação associada com a ausência de detecção de fatores relacionados à resposta tipo Th1, mostrando que estas avaliações podem ser importantes para o controle de cura da infecção pelo T. cruzi, demonstrando assim, o benefício do tratamento bem sucedido.
Myenteric plexus is differentially affected by infection with distinct Trypanosoma cruzi strains in Beagle dogs.
(2014) Paiva, Nívia Carolina Nogueira de; Fonseca, Kátia da Silva; Vieira, Paula Melo de Abreu; Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Moura, Sandra Aparecida Lima de; Veloso, Vanja Maria; Guedes, Paulo Marcos da Matta; Tafuri, Washington Luiz; Bahia, Maria Terezinha; Carneiro, Cláudia Martins
Chagasic megaoesophagus and megacolon are characterised by motor abnormalities related to enteric nervous system lesions and their development seems to be related to geographic distribution of distinct Trypanosoma cruzi subpopulations. Beagle dogs were infected with Y or Berenice-78 (Be-78) T. cruzi strains and necropsied during the acute or chronic phase of experimental disease for post mortem histopathological evaluation of the oesophagus and colon. Both strains infected the oesophagus and colon and caused an inflammatory response during the acute phase. In the chronic phase, inflammatory process was observed exclusively in the Be-78 infected animals, possibly due to a parasitism persistent only in this group. Myenteric denervation occurred during the acute phase of infection for both strains, but persisted chronically only in Be-78 infected animals. Glial cell involvement occurred earlier in animals infected with the Y strain, while animals infected with the Be-78 strain showed reduced glial fibrillary acidic protein immunoreactive area of enteric glial cells in the chronic phase. These results suggest that although both strains cause lesions in the digestive tract, the Y strain is associated with early control of the lesion, while the Be-78 strain results in progressive gut lesions in this model.
Myocardial scars correlate with eletrocardiographic changes in chronic Trypanosoma cruzi infection for dogs treated with Benznidazole.
(2013) Caldas, Ivo Santana; Guedes, Paulo Marcos da Matta; Santos, Fabiane Matos dos; Diniz, Lívia de Figueiredo; Martins, Tassiane Assíria Fontes; Nascimento, Alvaro Fernando da Silva do; Azevedo, Maíra Araújo; Lima, Wanderson Geraldo de; Nascimento Neto, Raimundo Marques do; Torres, Rosália Morais; Silva, André Talvani Pedrosa da; Bahia, Maria Terezinha
objectives The cardiac form of Chagas disease is evidenced by a progressive cardiac inflammation that leads to myocarditis, fibrosis and electrocardiographic (ECG) conduction abnormalities. Considering these characteristics, the aim of this study was to prospectively evaluate the early ECG changes in dogs that were experimentally inoculated with Benznidazole (Bz)-susceptibly (Berenice-78) and Bz-resistant (VL-10, and AAS) Trypanosoma cruzi strains and, later, evaluate the efficacy of Bz treatment for preventing these ECG alterations. methods Electrocardiographic changes of treated and untreated animals were prospectively evaluated for up to 270 days after infection, at which point collagen (right atrium) quantification was performed. results All infected dogs had a high intensity of heart fibrosis (4616.00 ± 1715.82 collagen ⁄ 74931 lm2 in dogs infected with Berenice-78 strain, 5839.2 ± 1423.49 collagen ⁄ 74931 lm2 in infected by AAS and 6294.40 ± 896.04 collagen ⁄ 74931 lm2 in animals infected with VL-10 strain), while 78.57% of all infected dogs showed ECG alterations. Bz Therapy reduced or prevented fibrosis in Bz-susceptible Berenice-78 (2813.00 ± 607.13 collagen ⁄ 74931 lm2) and Bz-resistant AAS strains (4024 ± 1272.44 collagen ⁄ 74931 lm2), coincident with only 10% de ECG alterations at 270 days. However, in those animals infected with a Bz-resistant VL-10 strain, specific treatment did not alter collagen deposition (6749.5 ± 1596.35 collagen ⁄ 74931 lm2) and there was first atrioventricular block and chamber overload at 120 and 270 days after infection, with 75% abnormal ECG exams. conclusions These findings indicate that an effective antiparasitic treatment in the early stage of Chagas disease can lead to a significant reduction in the frequency and severity of the parasite-induced cardiac disease, even if parasites are not completely eliminated.
Myocarditis in different experimental models infected by Trypanosoma cruzi is correlated with the production of IgG1 isotype.
(2017) Caldas, Ivo Santana; Diniz, Lívia de Figueiredo; Guedes, Paulo Marcos da Matta; Nascimento, Álvaro Fernando da Silva do; Galvão, Lúcia Maria da Cunha; Lima, Wanderson Geraldo de; Caldas, Sérgio; Bahia, Maria Terezinha
This study was designed to verify the relationship between IgG antibodies isotypes and myocarditis inTrypanosoma cruzi infection using mice and dogs infected with different T. cruzi strains. The animals wereinfected with benznidazole-susceptible Berenice-78 and benznidazole-resistant AAS and VL-10 strains.The IgG subtypes were measured in serum samples from dogs (IgG, IgG1, and IgG2) and mice (IgG, IgG1,IgG2a, and IgG2b). The infection of dogs with VL-10 strain induced the highest levels of heart inflammationwhile intermediate and lower levels were detected with Berenice-78 and AAS strains, respectively. Similarresults were found in mice infected with VL-10, but not in those infected with AAS or Berenice-78 strains.The AAS strain induced higher levels of heart inflammation in mice, while Berenice-78 strain was notable to induce it. Correlation analysis between myocarditis and antibody reactivity index revealed veryinteresting results, mainly for IgG and IgG1, the latter being the most exciting. High IgG1 showed asignificant correlation with myocarditis in both experimental models, being more significant in dogs(r = 0.94, p < 0.0001) than in mice (r = 0.58, p = 0.047). Overall, our data suggest that IgG1 could be a goodmarker to demonstrate myocarditis intensity in Chagas disease.©
Naturally Leishmania infantum-infected dogs display an overall impairment of chemokine and chemokine receptor expression during visceral leishmaniasis.
(2013) Nascimento, Manuela Sales Lima; Albuquerque, Talyta Delfino Rolim de; Matta, Maria Adelaide do Valle; Caldas, Ivo Santana; Diniz, Lívia de Figueiredo; Silva, André Talvani Pedrosa da; Bahia, Maria Terezinha; Andrade, Cléber Mesquita de; Galvão, Lúcia Maria da Cunha; Câmara, Antônia Cláudia Jácome da; Guedes, Paulo Marcos da Matta
Dogs are the primary reservoir for Leishmania parasites. The immune response induced by Leishmania infantum infection in these animals has not been completely elucidated, and few studies have investigated the relationship between the expression levels of chemokines and chemokine receptors and the clinical status of dogs with canine visceral leishmaniasis (CVL). The aim of this study was to correlate the clinical status of naturally L. infantuminfected dogs (from rural areas of Mossoró city, State of Rio Grande do Norte, Brazil) with the expression levels of chemokines (ccl1, ccl2, ccl3, ccl4, ccl5, ccl17, ccl20, ccl24, ccl26, cxcl9, cxcl10) and chemokine receptors (cxcr3, ccr3, ccr4, ccr5, ccr6, ccr8) in the liver and spleen determined using real-time PCR. Twenty-one dogs were clinically evaluated and classified as asymptomatic (n = 11) or symptomatic (n = 10). Splenomegaly, weight loss and onychogryphosis were the most pronounced symptoms. In the liver, the mRNA expression levels of ccl1, ccl17, ccl26, ccr3, ccr4, ccr5, ccr6, and ccr8 were lower in symptomatic animals than in asymptomatic animals. Compared with uninfected animals, symptomatic dogs had lower expression levels of almost all molecules analyzed. Moreover, high clinical scores were negatively correlated with ccr5 and ccr6 expression and positively correlated with cxcl10 expression. We conclude that the impairment of the expression of chemokines and chemokine receptors results in deficient leukocyte migration and hampers the immune response, leading to the development of disease.
Protein deficiency alters CX3CL1 and endothelin-1 in experimental Trypanosoma cruzi-induced cardiomyopathy.
(2013) Martins, Régia Ferreira; Martinelli, Patrícia Massara; Guedes, Paulo Marcos da Matta; Pádua, Bruno da Cruz; Santos, Fabiane Matos dos; Silva, Marcelo Eustáquio; Bahia, Maria Terezinha; Silva, André Talvani Pedrosa da
objective Chagas heart disease is developed as a result of the infection with Trypanosoma cruzi. Protein malnutrition contributes to secondary immunodeficiency. The aim of this study was to investigate the role of a low protein diet on the production of endothelin-1 and CX3CL1 in blood and cardiac tissue samples in an experimental model with T. cruzi infection. methods Fisher rats were submitted to low protein (6%) and normal protein (15%) diets and then infected with the Y strain of T. cruzi. At days 15 and 120, parasites and immune cells were evaluated. results The low protein diet reduced body weight and circulating serum proteins, but promoted elevation of CX3CL1 and endothelin-1 levels in infected animals, which were unable to control blood parasitemia replication. In heart tissue, the low protein diet reduced cardiac CX3CL1, endothelin-1 and leucocyte infiltration in the acute phase, in particular CD68 and CD163 macrophage phenotypes. conclusion Together, these results highlight the participation of endothelin-1 and CX3CL1 in the inflammatory process of Chagas diesease, both being mediators partially controlled by the host nutritional status.
The dog as model for chemotherapy of the Chagas’ disease.
(2002) Guedes, Paulo Marcos da Matta; Veloso, Vanja Maria; Tafuri, Washington Luiz; Galvão, Lúcia Maria da Cunha; Carneiro, Cláudia Martins; Lana, Marta de; Chiari, Egler; Soares, Killarney Ataide; Bahia, Maria Terezinha
In the present study, we investigated the role of dogs as experimental models for acute and chronic phases of Chagas’ disease, before and after therapeutic treatments. Dogs were infected with Trypanosoma cruzi strains of different susceptibilities to benznidazole (Bz) and treated with the same therapeutic scheme as used for human chagasic. The treatment with Bz was able to prevent death and induced parasitological cure in 62.5% (acute phase) and 38.7% (chronic recent phase) of the tested animals. These results were similar to those reported in clinical trials for treated human patients (cured and uncured) in both phases of the disease. We also showed that parasitologic and serologic tests for monitoring the cure were similar to those obtained for human trials. In addition, Polymerase chain reaction showed the highest sensitivity when compared with hemoculture as an indicator of parasite clearance. In conclusion, the proposed experimental model should be relevant for chemotherapy studies for the control of Chagas’ disease.
Trypanosoma cruzi : blood parasitism kinetics and their correlation with heart parasitism intensity during long-term infection of Beagle dogs.
(2008) Veloso, Vanja Maria; Guedes, Paulo Marcos da Matta; Andrade, Isabel Mayer de; Caldas, Ivo Santana; Martins, Helen Rodrigues; Carneiro, Cláudia Martins; Coelho, George Luiz Lins Machado; Lana, Marta de; Galvão, Lúcia Maria da Cunha; Bahia, Maria Terezinha; Chiari, Egler
The goals of the present study were to evaluate the kinetics of blood parasitism by examination of fresh blood, blood culture (BC) and PCR assays and their correlation with heart parasitism during two years of infection in Beagle dogs inoculated with the Be-78, Y and ABC Trypanosoma cruzi strains. Our results showed that the parasite or its kDNA is easily detected during the acute phase in all infected animals. On the other hand, a reduced number of positive tests were verified during the chronic phase of the infection. The frequency of positive tests was correlated with T. cruzi strain. The percentage of positive BC and blood PCR performed in samples from animals inoculated with Be-78 and ABC strains were similar and significantly larger in relation to animals infected with the Y strain. Comparison of the positivity of PCR tests performed using blood and heart tissue samples obtained two years after infection showed two different patterns associated with the inoculated T. cruzi strain: (1) high PCR positivity for both blood and tissue was observed in animals infected with Be-78 or ABC strains; (2) lower and higher PCR positivity for the blood and tissue, respectively, was detected in animals infected with Y strains. These data suggest that the sensitivity of BC and blood PCR was T. cruzi strain dependent and, in contrast, the heart tissue PCR revealed higher sensitivity regardless of the parasite stock.