Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukin-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells

ABSTRACTTrypanosoma cruzi, the agent of Chagas' disease, infects a variety of mammalian cells in a process that includes multiple cycles of intracellular division and differentiation starting with host receptor recognition by a parasite ligand(s). Earlier work in our laboratory showed that the neurotrophin-3 (NT-3) receptor TrkC is activated byT. cruzisurfacetrans-sialidase, also known as parasite-derived neurotrophic factor (PDNF). However, it has remained unclear whether TrkC is used byT. cruzito enter host cells. Here, we show that a neuronal cell line (PC12-NNR5) relatively resistant toT. cruzibecame highly susceptible to infection when overexpressing human TrkC but not human TrkB. Furthermore,trkCtransfection conferred an ∼3.0-fold intracellular growth advantage. Sialylation-deficient Chinese hamster ovarian (CHO) epithelial cell lines Lec1 and Lec2 also became much more permissive toT. cruziafter transfection with thetrkCgene. Additionally, NT-3 specifically blockedT. cruziinfection of the TrkC-NNR5 transfectants and of naturally permissive TrkC-bearing Schwann cells and astrocytes, as did recombinant PDNF. Two specific inhibitors of Trk autophosphorylation (K252a and AG879) and inhibitors of Trk-induced MAPK/Erk (U0126) and Akt kinase (LY294002) signaling, but not an inhibitor of insulin-like growth factor 1 receptor, abrogated TrkC-mediated cell invasion. Antibody to TrkC blockedT. cruziinfection of the TrkC-NNR5 transfectants and of cells that naturally express TrkC. The TrkC antibody also significantly and specifically reduced cutaneous infection in a mouse model of acute Chagas' disease. TrkC is ubiquitously expressed in the peripheral and central nervous systems, and in nonneural cells infected byT. cruzi, including cardiac and gastrointestinal muscle cells. Thus, TrkC is implicated as a functional PDNF receptor in cell entry, independently of sialic acid recognition, mediating broadT. cruziinfection bothin vitroandin vivo.

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In Vitro and In Vivo Activities of E5700 and ER-119884, Two Novel Orally Active Squalene Synthase Inhibitors, against Trypanosoma cruzi

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.7.2379-2387.2004 ◽

2004 ◽

Vol 48 (7) ◽

pp. 2379-2387 ◽

Cited By ~ 62

Author(s):

Julio A. Urbina ◽

Juan Luis Concepcion ◽

Aura Caldera ◽

Gilberto Payares ◽

Cristina Sanoja ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Public Health Problem ◽

Squalene Synthase ◽

Host Cells ◽

In Vivo Studies ◽

Inorganic Pyrophosphate ◽

Orally Active

ABSTRACT Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K i values in the low nanomolar to subnanomolar range in the absence or presence of 20 μM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease.

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Efficacy of Novel Pyrazolone Phosphodiesterase Inhibitors in Experimental Mouse Models of Trypanosoma cruzi

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00414-20 ◽

2020 ◽

Vol 64 (9) ◽

Author(s):

Julianna Siciliano de Araújo ◽

Cristiane França da Silva ◽

Denise da Gama Jaén Batista ◽

Aline Nefertiti ◽

Ludmila Ferreira de Almeida Fiuza ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Phosphodiesterase Inhibitors ◽

Biological Properties ◽

Host Cells ◽

Mammalian Host ◽

Intracellular Camp ◽

Additive Interaction ◽

Content Type

ABSTRACT Pyrazolones are heterocyclic compounds with interesting biological properties. Some derivatives inhibit phosphodiesterases (PDEs) and thereby increase the cellular concentration of cyclic AMP (cAMP), which plays a vital role in the control of metabolism in eukaryotic cells, including the protozoan Trypanosoma cruzi, the etiological agent of Chagas disease (CD), a major neglected tropical disease. In vitro phenotypic screening identified a 4-bromophenyl-dihydropyrazole dimer as an anti-T. cruzi hit and 17 novel pyrazolone analogues with variations on the phenyl ring were investigated in a panel of phenotypic laboratory models. Potent activity against the intracellular forms (Tulahuen and Y strains) was obtained with 50% effective concentration (EC50) values within the 0.17 to 3.3 μM range. Although most were not active against bloodstream trypomastigotes, an altered morphology and loss of infectivity were observed. Pretreatment of the mammalian host cells with pyrazolones did not interfere with infection and proliferation, showing that the drug activity was not the result of changes to host cell metabolism. The pyrazolone NPD-227 increased the intracellular cAMP levels and was able to sterilize T. cruzi-infected cell cultures. Thus, due to its high potency and selectivity in vitro, and its additive interaction with benznidazole (Bz), NPD-227 was next assessed in the acute mouse model. Oral dosing for 5 days of NPD-227 at 10 mg/kg + Bz at 10 mg/kg not only reduced parasitemia (>87%) but also protected against mortality (>83% survival), hence demonstrating superiority to the monotherapy schemes. These data support these pyrazolone molecules as potential novel therapeutic alternatives for Chagas disease.

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Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity

10.21203/rs.2.21521/v1 ◽

2020 ◽

Author(s):

Nieves Martinez-Peinado ◽

Nuria Cortes-Serra ◽

Laura Torras-Claveria ◽

Maria-Jesus Pinazo ◽

Joaquim Gascon ◽

...

Keyword(s):

Natural Products ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

New Drugs ◽

Host Cells ◽

Amaryllidaceae Alkaloids ◽

Cytotoxicity Assays ◽

Limited Efficacy ◽

Single Compound ◽

New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti- T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family. Methods: the activity of each alkaloid was assessed by means of a newly developed anti- T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity. Results: we identified a single compound (hippeastrine 2 ) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

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Dispersal patterns of Trypanosoma cruzi in Arequipa, Peru

10.1101/838235 ◽

2019 ◽

Author(s):

Alexander S.F. Berry ◽

Renzo Salazar-Sánchez ◽

Ricardo Castillo-Neyra ◽

Katty Borrini-Mayorí ◽

Claudia Arevalo-Nieto ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Causative Agent ◽

Animal Movement ◽

Protozoan Parasite ◽

Domestic Animal ◽

Urban Environments ◽

Urban Landscapes ◽

Population Genomic ◽

The City

AbstractAnthropogenic environmental alterations such as urbanization can threaten native populations as well as create novel environments that allow human pests and pathogens to thrive. As the number and size of urban environments increase globally, it is more important than ever to understand the dispersal dynamics of hosts, vectors and pathogens of zoonotic disease systems. For example, a protozoan parasite and the causative agent of Chagas disease in humans, Trypanosoma cruzi, recently colonized and spread through the city of Arequipa, Peru. We used population genomic and phylogenomic tools to analyze whole genomes of 123 T. cruzi isolates collected throughout Arequipa to determine patterns of T. cruzi dispersal. The data show significant population genetic structure within city blocks-parasites in the same block tend to be very closely related - but no population structure among blocks within districts - parasites in neighboring blocks are no more closely related to one another than to parasites in distant districts. These data suggest that T. cruzi dispersal within a block occurs regularly and that occasional long-range dispersal events allow the establishment of new T. cruzi populations in distant blocks. Movement of domestic animals may be the primary mechanism of inter-block and inter-district T. cruzi dispersal.Author SummaryUrbanization creates environments that are ideal for some human pests and pathogens. As the number and size of urban environments increases globally, it is becoming vital to understand how human disease-causing pathogens, their vectors, and their non-human hosts disperse through urban landscapes. Here we study a population of Trypanosoma cruzi – the protozoan parasite and causative agent of Chagas disease in humans – that recently colonized the city of Arequipa, Peru. We use population genomic and phylogenomic tools to understand how this parasite population dispersed through the city to achieve its current distribution and abundance. We show that T. cruzi collected from the same city block tend to be very closely related, while those from neighboring blocks are often as distantly related as those from blocks in distant districts. The data suggest that vectors facilitate frequent within-block dispersal of the parasite, while domestic animal movement may facilitate the relatively infrequent inter-block and interdistrict dispersal.

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Bioluminescent:fluorescent Trypanosoma cruzi Reporter Strains as Tools for Exploring Chagas Disease Pathogenesis and Drug Activity

Current Pharmaceutical Design ◽

10.2174/1381612826666201124113214 ◽

2020 ◽

Vol 26 ◽

Author(s):

Martin C. Taylor ◽

Alexander I. Ward ◽

Francisco Olmo ◽

Amanda F. Francisco ◽

Shiromani Jayawardhana ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Parasite Burden ◽

New Drugs ◽

Host Cells ◽

Complex Nature ◽

Disease Pathogenesis ◽

Drug Activity ◽

Cellular Environment

: Chagas disease results from infection with the trypanosomatid parasite Trypanosoma cruzi. Progress in developing new drugs has been hampered by the long term and complex nature of the condition and by our limited understanding of parasite biology. Technical difficulties in assessing the parasite burden during the chronic stage of infection have also proved to be a particular challenge. In this context, the development of non-invasive, highly sensitive bioluminescence imaging procedures, based on parasites that express a red-shifted luciferase, has greatly enhanced our ability to monitor infections in experimental models. Applications of this methodology have led to new insights into tissue tropism and infection dynamics, and have been a major driver in drug development. The system has been further modified by the generation of parasite reporter lines that express bioluminescent:fluorescent fusion proteins, an advance that has allowed chronic infections in mice to be examined at a cellular level. By exploiting bioluminescence to identify the rare sites of tissue infection, and fluorescence to detect T. cruzi at the level of individual host cells in histological sections, it has been possible to investigate the replication and differentiation status of parasites in vivo and to examine the cellular environment of infection foci. In combination, these data are providing a framework for the detailed dissection of disease pathogenesis and drug activity.

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Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity

10.21203/rs.2.21521/v2 ◽

2020 ◽

Author(s):

Nieves Martinez-Peinado ◽

Nuria Cortes-Serra ◽

Laura Torras-Claveria ◽

Maria-Jesus Pinazo ◽

Joaquim Gascon ◽

...

Keyword(s):

Natural Products ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Specific Activity ◽

New Drugs ◽

Host Cells ◽

Amastigote Stage ◽

Limited Efficacy ◽

Single Compound ◽

New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti- T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family. Methods: the activity of each alkaloid was assessed by means of an anti- T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity. Results: we identified a single compound (hippeastrine 2 ) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Moreover, it showed specific activity against the amastigote stage (IC 50 = 3.31 μM). Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

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Discovery and Optimization of a Compound Series Active against Trypanosoma cruzi, the Causative Agent of Chagas Disease

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.9b01852 ◽

2020 ◽

Vol 63 (6) ◽

pp. 3066-3089

Author(s):

Justin R. Harrison ◽

Sandipan Sarkar ◽

Shahienaz Hampton ◽

Jennifer Riley ◽

Laste Stojanovski ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Causative Agent ◽

Compound Series

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Comparative high-throughput analysis of the Trypanosoma cruzi response to organometallic compounds

Metallomics ◽

10.1039/d0mt00030b ◽

2020 ◽

Vol 12 (5) ◽

pp. 813-828

Author(s):

M. Florencia Mosquillo ◽

Pablo Smircich ◽

Martín Ciganda ◽

Analía Lima ◽

Dinorah Gambino ◽

...

Keyword(s):

Gene Expression ◽

Trypanosoma Cruzi ◽

Expression Pattern ◽

Chagas Disease ◽

High Throughput ◽

Causative Agent ◽

Gene Expression Pattern ◽

Organometallic Compounds ◽

Global Gene Expression ◽

High Throughput Analysis

An in-depth, comparative look at the effects of two structurally related organometallic Pd and Pt compounds on the global gene expression pattern of T. cruzi epimastigotes. This parasite is the causative agent of Chagas disease.

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