The Colombian Strain of Trypanosoma cruzi Induces a Proinflammatory Profile, Neuronal Death, and Collagen Deposition in the Intestine of C57BL/6 Mice Both during the Acute and Early Chronic Phase

The objective of this study was to evaluate the histopathological changes caused by infection with the Colombian strain of Trypanosoma cruzi (T. cruzi) in the acute and chronic experimental phases. C57Bl/6 mice were infected with 1000 trypomastigote forms of the Colombian strain of T. cruzi. After 30 days (acute phase) and 90 days (early chronic phase) of infection, the animals were euthanized, and the colon was collected and divided into two parts: proximal and distal. The distal portion was used for histopathological analysis, whereas the proximal portion was used for quantification of pro- and anti-inflammatory cytokines. In addition, the weight of the animals and parasitemia were assessed. The infection induced gradual weight loss in the animals. In addition, the infection induced an increase in interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α) in the intestine in the acute phase, in which this increase continued until the early chronic phase. The same was observed in relation to the presence of intestinal inflammatory infiltrates. In relation to interleukin (IL)-10, there was an increase only in the early chronic phase. The Colombian strain infection was also able to induce neuronal loss in the myenteric plexus and deposition of the collagen fibers during the acute phase. The Colombian strain of T. cruzi is capable of causing histopathological changes in the intestine of infected mice, especially in inducing neuronal destructions. Thus, this strain can also be used to study the intestinal form of Chagas disease in experimental models.

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The effect of memantine, an antagonist of the NMDA glutamate receptor, in in vitro and in vivo infections by Trypanosoma cruzi

10.1101/546861 ◽

2019 ◽

Author(s):

Higo Fernando Santos Souza ◽

Sandra Carla Rocha ◽

Flávia Silva Damasceno ◽

Ludmila Nakamura Rapado ◽

Elisabeth Mieko Furusho Pral ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Side Effects ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Glutamate Receptor ◽

Acute Phase ◽

Chronic Phase ◽

Parasitic Load ◽

Inflammatory Infiltrates

AbstractChagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5-6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversion in infected people when used in the acute phase; however, their use in the chronic phase (the time when the majority of cases are diagnosed) is limited due to their serious side effects. Memantine is a glutamate receptor antagonist in the central nervous system of mammals that has been used for the treatment of Alzheimer’s disease. Our group previously reported memantine as a trypanocidal drug that is able to induce apoptosis-like death in T. cruzi. In the present work, we further investigated the effects of memantine on the infection of RAW 264.7 macrophages in vivo (in BALB/c mice). Here, we showed that memantine is able to diminish NO and Ca2+ entry in both LPS-activated and non-activated cells. These results, together with the fact that memantine was also able to reduce the infection of macrophages, led us to propose that this drug is able to activate a pro-oxidant non-NO-dependent cell defense mechanism. Finally, infected mice that were treated with memantine had diminished parasitemia, cardiac parasitic load, and inflammatory infiltrates. In addition, the treated mice had an increased survival rate. Taken together, these results indicate memantine to be a candidate drug for the treatment of Chagas disease.Author summaryChagas disease affects approximately 5 million people and is caused by the protist parasite Trypanosoma cruzi. Until now, there are no vaccines to prevent the human infection, and the therapy relies on the use of two drugs discovered more than 50 years ago, nifurtimox and benznidazole. Both drugs are efficient during the acute phase of the disease, however their efficacy in the chronic phase, when most of patients are diagnosed is controversial. In addition, both drugs are toxic, causing severe side effects during the treatment. For these reasons, new drugs against T. cruzi are urgently needed. In this work, we report a series of experiments supporting the repositioning of memantine, a drug used for treating Alzheimer’s disease, to treat the T. cruzi infection in an experimental infection model. Our data show that infected mice treated with memantine have diminished their parasitemia, cardiac parasitic load and inflammatory infiltrates and more importantly, they have diminished their mortality. Taken together, these results prompt memantine as a promising drug for treating Chagas disease.

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Combined treatment with benznidazole and allopurinol in mice infected with a virulentTrypanosoma cruziisolate from Nicaragua

Parasitology ◽

10.1017/s0031182013000176 ◽

2013 ◽

Vol 140 (10) ◽

pp. 1225-1233 ◽

Cited By ~ 10

Author(s):

NOELIA L. GROSSO ◽

MICAELA LOPEZ ALARCON ◽

JAQUELINE BUA ◽

SUSANA A. LAUCELLA ◽

ADELINA RIARTE ◽

...

Keyword(s):

Survival Rate ◽

Trypanosoma Cruzi ◽

Endemic Area ◽

Low Dose ◽

Combined Treatment ◽

Chronic Phase ◽

Experimental Models ◽

Specific Antibodies ◽

Histopathological Studies ◽

Virulent Parasite

SUMMARYWe evaluated the effect of chemotherapy with a sequential combined treatment of a low dose of benznidazole and allopurinol, in different schedules of administration, in experimental models of acute and chronicTrypanosoma cruziinfection. Mice were infected with NicaraguaT. cruziisolate, a virulent parasite from an endemic area of Nicaragua, genotyped asTcI (Grossoet al. 2010). We assessed survival rate, IgG levels, histopathological studies and quantified parasitaemia. A 15% survival rate was recorded in untreated mice during the acute phase ofT. cruziinfection. Allopurinol administered immediately after benznidazole treatment was able to reduce parasitaemia and attenuate tissue damage by reducing inflammation.Trypanosoma cruzi-specific antibodies also decreased in 40–50% of the treated mice. The addition of allopurinol during the chronic phase showed the highest beneficial effect, not only by reducing parasitaemia but also by lowering the degree of inflammation and fibrosis.

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Effects of betamethasone on the course of experimentai. Infection with Trypanosoma cruzi

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86821986000300006 ◽

1986 ◽

Vol 19 (3) ◽

pp. 161-164 ◽

Cited By ~ 5

Author(s):

Frederico G.C. Abath ◽

Yara M. Gomes ◽

Eridan M. Coutinho ◽

Silvia M.L. Montenegro ◽

Maria E.B. Melo ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Acute Phase ◽

Bacterial Infections ◽

Acute Infection ◽

Chronic Phase ◽

Control Group ◽

Cumulative Mortality ◽

Histopathological Findings ◽

Experimental Group

In this experiment, the effect of betamethasone administered in the early post- acute infection of mice by Trypanosoma cruzi was studied. This drug was administered during 30 days after the 42nd day of infection in a dose of 0.15 mg/day. The betamethasone treatment did not cause fresh outbreaks of parasitemia and the histopathological findings in the chronic phase were not different from those in the control group. The higher cumulative mortality after treatment in the experimental group was due to superimposed bacterial infections. Outbred albino mice infected with low numbers ofY strain Trypanosoma cruzi trypomastigotes were not suitable models for Chagas' disease, since after 7 months of observation only mild histological lesions developed in all the animais. Prolonged betamethasone treatment of mice infected with low numbers o/Trypanosoma cruzi of the Y strain, during the post-acute phase did not aggravate the course of infection.

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Evolution of subpatent parasitaemia in Trypanosoma cruzi chronically infected mice with the help of a cyclophosphamide amplification transfer assay

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46651991000600013 ◽

1991 ◽

Vol 33 (6) ◽

pp. 509-514 ◽

Cited By ~ 1

Author(s):

José M. Alvarez ◽

Ayumi Oshima ◽

Veronica Mozer ◽

Liliane Guimarães ◽

Hércules Menezes

Keyword(s):

Trypanosoma Cruzi ◽

Acute Phase ◽

Chronic Phase ◽

Detection Tool ◽

Highly Sensitive ◽

Parasite Detection ◽

Cyclophosphamide Treatment ◽

One Year ◽

Cruzi Infection

We have evaluated the sensitivity of the classical blood subinoculation method, modified through cyclophosphamide treatment of transferred mice, for the detection of occult parasitaemias in Trypanosoma cruzi chronically infected mice. Besides its simplicity, the method was shown to be highly sensitive for both the "chronic" phase parasites (99% of chronic cases were shown to harbour occult parasitaemias) and for the acute phase parasites (T. cruzi could be detected in 53.8% of animals transferred with one Y strain parasite and in 20% of animals transferred with one CL strain parasite). Using acute phase bloodforms, the assay proved to be more sensitive than conventional subinoculation when dealing with the CL, but not the Y strain of the parasite. With the help of this parasite detection tool, we have studied during a one year period, the evolution of subpatent parasitaemias in a group of mice which survived through chemotherapy from lethal acute phase of T. cruzi infection. Cyclophosphamide transfer assay revealed occult parasitaemias in 100% of the chronic animals, nevertheless, continuous and discontinuous patterns of positivity were observed.

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Trypanosoma cruzi and experimental Chagas' disease: characterization of a stock isolated from a patient with associated digestive and cardiac form

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86821993000100006 ◽

1993 ◽

Vol 26 (1) ◽

pp. 25-33 ◽

Cited By ~ 7

Author(s):

E.C. Oliveira ◽

M.M.A. Stefani ◽

A.O. Luquetti ◽

E.F. Vêncio ◽

M.A.R. Moreira ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Digestive Tract ◽

Chagas Disease ◽

Acute Phase ◽

Experimental Infection ◽

Post Infection ◽

Chronic Phase ◽

Igg Antibodies ◽

Histopathology Examination

A new Trypanosoma cruzi stock isolated from a patient in the chronic phase of Chagas' disease with the digestive and cardiac fortn of the disease was characterized by experimental infection in isogenic, susceptible, A/Sn strain mice. Parasitemia curves showed up to 1.7x10(6) parasites/ml and no mortality was observed up to 300 days post infection. Specific IgM was found in mice in the acute phase up to 40 days and also in the chronic phase. IgG antibodies yvere detected in the acute and chronic phase. Histopathology examination demonstrated myotropism to the digestive tract muscle layers and to the heart.

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Trypanosoma cruzi infection associated with atypical clinical manifestation during the acute phase of the Chagas disease

Parasites & Vectors ◽

10.1186/s13071-019-3766-3 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Lucia Rangel-Gamboa ◽

Lirio López-García ◽

Francisco Moreno-Sánchez ◽

Irma Hoyo-Ulloa ◽

María Elisa Vega-Mémije ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Acute Phase ◽

Clinical Manifestations ◽

Chronic Phase ◽

Clinical History ◽

Skin Lesions ◽

Small Subunit ◽

Serological Tests ◽

Cutaneous Manifestations

Abstract Background Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi and is transmitted by triatomine insects. Clinical manifestations vary according to the phase of the disease. Cutaneous manifestations are usually observed in the acute phase (chagoma and Romaña’s sign) or after reactivation of the chronic phase by immunosuppression; however, a disseminated infection in the acute phase without immunosuppression has not been reported for CD. Here, we report an unusual case of disseminated cutaneous infection during the acute phase of CD in a Mexican woman. Methods Evaluation of the patient included a complete clinical history, a physical exam, and an exhaustive evaluation by laboratory tests, including ELISA, Western blot and PCR. Results Skin biopsies of a 50-year-old female revealed intracellular parasites affecting the lower extremities with lymphangitic spread in both legs. The PCR tests evaluated biopsy samples obtained from the lesions and blood samples, which showed a positive diagnosis for T. cruzi. Partial sequencing of the small subunit ribosomal DNA correlated with the genetic variant DTU II; however, serological tests were negative. Conclusions We present a case of CD with disseminated skin lesions that was detected by PCR and showed negative serological results. In Mexico, an endemic CD area, there are no records of this type of manifestation, which demonstrates the ability of the parasite to initiate and maintain infections in atypical tissues.

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BloodstreamTrypanosoma cruziparasites from mice simultaneously express antigens that are markers of acute and chronic human Chagas disease

Parasitology ◽

10.1017/s0031182000064337 ◽

1991 ◽

Vol 102 (3) ◽

pp. 379-385 ◽

Cited By ~ 8

Author(s):

M. S. Leguizamon ◽

O. E. Campetella ◽

M. B. Reyes ◽

C. F. Ibañez ◽

M. A. Basombrio ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Acute Phase ◽

Early Period ◽

Chronic Phase ◽

Blood Parasites ◽

Expression Library ◽

Antibody Specificities ◽

Human Infections ◽

Parasite Strains

Several recombinantTrypanosoma cruziproteins previously isolated were used as antigens to analyse antibody specificities present in sera from human infections. Some parasite proteins such as SAPA (Shed Acute Phase Antigen) are antigenic early after infection. Others, like antigens 1 and 30, are antigenic mainly during the chronic phase of the infection. To understand why different proteins are antigenic at different periods of infection, specificities of antibodies present in the sera of infected mice were compared with the antigens expressed by parasites collected directly from blood. Parasites collected during the acute parasitaemia peak expressed not only antigen SAPA, but also antigens 1 and 30. However, only antibodies against SAPA were frequently observed during the early period and also in the chronic phase of murine infection. Long-lasting antibodies against SAPA were detected regardless of the mouse and parasite strains used. Furthermore, all 8 recombinant clones detected in aT. cruziexpression library with pooled sera from acutely infected mice were homologous to the SAPA gene. These results show that even though parasites from the acute parasitaemia peak in mice may express simultaneously several proteins known to be antigenic, only antibodies against SAPA were consistently detected.

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Correlation between intestinal BMP2, IFNγ, and neural death in experimental infection with Trypanosoma cruzi

PLoS ONE ◽

10.1371/journal.pone.0246692 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0246692

Author(s):

José Rodrigues do Carmo Neto ◽

Marcos Vinicius da Silva ◽

Yarlla Loyane Lira Braga ◽

Arthur Wilson Florencio da Costa ◽

Simone Gonçalves Fonseca ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Acute Phase ◽

Myenteric Plexus ◽

Neuronal Damage ◽

Chronic Phase ◽

Late Complications ◽

Morphogenetic Protein ◽

Tnf Α ◽

Inflammatory Profile

Megacolon is one of the main late complications of Chagas disease, affecting approximately 10% of symptomatic patients. However, studies are needed to understand the mechanisms involved in the progression of this condition. During infection by Trypanosoma cruzi (T. cruzi), an inflammatory profile sets in that is involved in neural death, and this destruction is known to be essential for megacolon progression. One of the proteins related to the maintenance of intestinal neurons is the type 2 bone morphogenetic protein (BMP2). Intestinal BMP2 homeostasis is directly involved in the maintenance of organ function. Thus, the aim of this study was to correlate the production of intestinal BMP2 with immunopathological changes in C57Bl/6 mice infected with the T. cruzi Y strain in the acute and chronic phases. The mice were infected with 1000 blood trypomastigote forms. After euthanasia, the colon was collected, divided into two fragments, and a half was used for histological analysis and the other half for BMP2, IFNγ, TNF-α, and IL-10 quantification. The infection induced increased intestinal IFNγ and BMP2 production during the acute phase as well as an increase in the inflammatory infiltrate. In contrast, a decreased number of neurons in the myenteric plexus were observed during this phase. Collagen deposition increased gradually throughout the infection, as demonstrated in the chronic phase. Additionally, a BMP2 increase during the acute phase was positively correlated with intestinal IFNγ. In the same analyzed period, BMP2 and IFNγ showed negative correlations with the number of neurons in the myenteric plexus. As the first report of BMP2 alteration after infection by T. cruzi, we suggest that this imbalance is not only related to neuronal damage but may also represent a new route for maintaining the intestinal proinflammatory profile during the acute phase.

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Suppression of humoral immunity and lymphocyte responsiveness during experimental trypanosoma cruzi infections

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46651984000200001 ◽

1984 ◽

Vol 26 (2) ◽

pp. 67-77 ◽

Cited By ~ 10

Author(s):

José A. O'daly ◽

Simonetta Simonis ◽

Nelva De Rolo ◽

Henry Caballero

Keyword(s):

Trypanosoma Cruzi ◽

Lymph Nodes ◽

Acute Phase ◽

Chronic Phase ◽

Complete Recovery ◽

Partial Recovery ◽

Splenic Lymphocytes ◽

Humoral Immune ◽

Intracellular Parasites ◽

Spleen And Lymph Nodes

C3H/He and C57B1/6 mice were inoculated with 500 Trypanosoma cruzi trypomastigotes (Strain Y). During the acute phase infected mice presented parasitemia and enlargement of lymph nodes and spleens and intracellular parasites were observed in the heart. Examinations of cells derived from spleen and lymph nodes showed increased numbers of IgM and IgG-bearing cells. During the peak of splenomegaly, about day 17 post-infections, splenic lymphocytes showed a marked decrease in responsiveness to T and B-cell mitogens, parasite antigens and plaque forming cells (PFC) to sheep red blood cells (SRBC). Unfractionated or plastic adherent splenic cells from mice, obtained during the acute phase were able to suppress the response to mitogens by lymphocytes from uninfected mice. During the chronic phase. Disappearance of parasitemia and intracellular parasites in the hearts as well as a decrease in spleen size, was observed. These changes preceded the complete recovery of responsiveness to mitogens and T. cruzi antigens by C57B1/6 splenic lymphocytes. However, this recovery was only partial in the C3H/He mice, known to be more sensitive to T. cruzi infection. Partial recovery of humoral immune response also occurred in both strains of mice during the chronic phase.

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Resting and Dynamic Electrocardiography in Dogs with Experimental Chagas Cardiomyopathy

Epidemiology Research International ◽

10.1155/2012/153539 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

R. Oliveira Alves ◽

A. A. Camacho ◽

D. P. Junior

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Acute Phase ◽

Sinus Tachycardia ◽

Chronic Phase ◽

Left Ventricular ◽

Sinus Arrest ◽

Chagas Cardiomyopathy ◽

Electrocardiographic Monitoring ◽

Electrocardiographic Changes

In the present protocol, adult dogs were infected with Trypanosoma cruzi, Bolivian strain, in order to show electrocardiographic changes by means of resting and dynamic (Holter) methods during acute and chronic phases of Chagas disease. In the acute phase there were sinus tachycardia, atrial and left ventricular overload, millivoltage suppression, electric alternance, and episodes of sinus arrest. At the parasitemia peak, atrium-ventricular block, junctional escape complexes, and atrium-ventricular dissociation were observed. Dogs that presented the most serious arrhythmias died suddenly. The increase in supraventricular and ventricular arrhythmic events, concentrated in the 4th postinoculation week, was visible at electrocardiographic monitoring. In the chronic phase, the events were restricted to first-degree atrium-ventricular blocks, premature ventricular complexes, ventricular bigeminy, and electrical alternation. It was concluded that the computerized and dynamic electrocardiography allowed to diagnose transient arrhythmia and to observe that the main tachyarrhythmic changes are concentrated at the acute phase concomitantly to the parasitemia peak.

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