signature=e7ffd10a51e200accf41a200626ab7f4,Identification of Anti-Trypanosoma cruzi Lead Compounds w...

.2018 Mar 27;62(4):e01834-17.

doi: 10.1128/AAC.01834-17.

Print 2018 Apr.

Identification of Anti-Trypanosoma cruzi Lead Compounds with Putative Immunomodulatory Activity

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1 Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.

2 Programa de Pós-graduação em Sanidade e Produção Animal nos Trópicos, Medicina Veterinária, Universidade de Uberaba (UNIUBE), Uberaba, Minas Gerais, Brazil.

3 Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

4 Departamento de Propedêutica Complementar, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

5 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California, USA.

6 Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil atcteixeira@gmail.com.

# Contributed equally.

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Identification of Anti-Trypanosoma cruzi Lead Compounds with Putative Immunomodulatory Activity

Dayane Andriotti Ottaet al.

Antimicrob Agents Chemother.

2018.

Free PMC article

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.2018 Mar 27;62(4):e01834-17.

doi: 10.1128/AAC.01834-17.

Print 2018 Apr.

Affiliations

1 Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.

2 Programa de Pós-graduação em Sanidade e Produção Animal nos Trópicos, Medicina Veterinária, Universidade de Uberaba (UNIUBE), Uberaba, Minas Gerais, Brazil.

3 Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

4 Departamento de Propedêutica Complementar, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

5 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California, USA.

6 Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil atcteixeira@gmail.com.

# Contributed equally.

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Abstract

In seeking substitutions for the current Chagas disease treatment, which has several relevant side effects, new therapeutic candidates have been extensively investigated. In this context, a balanced interaction between mediators of the host immune response seems to be a key element for therapeutic success, as a proinflammatory microenvironment modulated by interleukin-10 (IL-10) is shown to be relevant to potentiate anti-Trypanosoma cruzi drug activity. This study aimed to identify the potential immunomodulatory activities of the anti-T. cruzi K777, pyronaridine (PYR), and furazolidone (FUR) compounds in peripheral blood mononuclear cells (PBMC) from noninfected (NI) subjects and chronic Chagas disease (CD) patients. Our results showed low cytotoxicity to PBMC populations, with 50% cytotoxic concentrations (CC50) of 71.0 μM (K777), 9.0 μM (PYR), and greater than 20 μM (FUR). In addition, K777 showed no impact on the exposure index (EI) of phytohemagglutinin-stimulated leukocytes (PHA), while PYR and FUR treatments induced increased EI of monocytes and T lymphocytes at late stages of apoptosis in NI subjects. Moreover, K777 induced a more prominent proinflammatory response (tumor necrosis factor alpha-positive [TNF-α+] CD8+/CD4+, gamma interferon-positive [IFN-γ+] CD4+/CD8+ modulated by interleukin-10-positive [IL-10+] CD4+ T/CD8+ T) than did PYR (TNF-α+ CD8+, IL-10+ CD8+) and FUR (TNF-α+ CD8+, IL-10+ CD8+). Signature analysis of intracytoplasmic cytokines corroborated the proinflammatory/modulated (K777) and proinflammatory (PYR and FUR) profiles previously found. In conclusion, the lead compound K777 may induce beneficial changes in the immunological profile of patients presenting the chronic phase of Chagas disease and may contribute to a more effective therapy against the disease.

Keywords:

Chagas disease; Trypanosoma cruzi; immunomodulation; screening compounds.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Viability of peripheral blood mononuclear…

FIG 1

Viability of peripheral blood mononuclear cells (PBMC) from healthy subjects (NI, n =…

FIG 1

Viability of peripheral blood mononuclear cells (PBMC) from healthy subjects (NI, n = 12) after 72-h in vitro treatment with reference drug BZ and K777, PYR, and FUR anti-T. cruzi lead compounds by alamarBlue. Data are presented as means ± standard errors of the means (SEM). Significance is indicated by asterisks: P < 0.05 (*), P < 0.01 (**), and P < 0.001 (***).

FIG 2

Drug-induced changes on in vitro…

FIG 2

Drug-induced changes on in vitro apoptotic cell death and intracytoplasmic cytokine profile of…

FIG 2

Drug-induced changes on in vitro apoptotic cell death and intracytoplasmic cytokine profile of peripheral blood mononuclear cells (PBMC) from healthy subjects. The results are presented as the means ± SEM of exposure index (EI = value for treated cultures/value for control cultures) of PBMC measured from cultures treated with BZ, K777, PYR, and FUR from NI subjects (n = 18). Statistically significant differences between populations undergoing the same treatment are represented by a solid black line. Significant differences for the same population between different treatments tested compared to BZ are represented by a gray rectangle.

FIG 3

Drug-induced changes on in vitro…

FIG 3

Drug-induced changes on in vitro apoptotic cell death and intracytoplasmic cytokine profile of…

FIG 3

Drug-induced changes on in vitro apoptotic cell death and intracytoplasmic cytokine profile of peripheral blood mononuclear cells (PBMC) from Chagas disease patients. The results are presented as the means ± SEM of exposure index (EI = value for treated cultures/value for control cultures) of PBMC from CD patients (n = 20) measured from cultures treated with BZ, K777, PYR, and FUR. Statistically significant differences between populations undergoing the same treatment are represented by a solid black line (segment). Significant differences for the same population subjected to different treatments tested compared to BZ are represented by a gray rectangle.

FIG 4

Drug-induced changes on in vitro…

FIG 4

Drug-induced changes on in vitro overall signature of high cytokine producers. Signatures of…

FIG 4

Drug-induced changes on in vitro overall signature of high cytokine producers. Signatures of high frequency of cytokine-producing cells from innate (CD14) and adaptive (CD4, CD8, CD19) immune compartments by noninfected subjects (NI, n = 18) and Chagas disease patients (CD, n = 20) after treatment with BZ (blue bars), K777 (red bars), PYR (green bars), and FUR (pink bars) lead compounds. The ascendant frequency of cytokine-producing cells from innate and adaptive immune compartments in each group is represented by bars. Dotted lines represent the 50th percentile that was used as a cutoff to identify relevant differences. The results are presented as exposure index (EI = value for treated cultures/value for control cultures).

FIG 5

Drug-induced changes on in vitro…

FIG 5

Drug-induced changes on in vitro intracytoplasmic cytokine signatures of innate and adaptive immunity.…

FIG 5

Drug-induced changes on in vitro intracytoplasmic cytokine signatures of innate and adaptive immunity. Radar graphs represent the balance of subjects with a high frequency of inflammatory (IL-2, TNF, IFN) or regulatory (IL-10, IL-4) cytokine-producing cells of innate (CD14) and adaptive (CD4, CD8, CD19) immunity. Graphs were constructed with each axis displaying the proportion of subjects with a high frequency of cytokine-producing cells within a given leukocyte subset. The values of each axis can be joined to form the central polygon area that represents the general inflammatory/regulatory cytokine balance. Increasing or decreasing central polygon areas reflect either higher or lower contributions, respectively, of the inflammatory versus regulatory cytokine balance in each group. Analysis of the radar chart axes highlights the contribution of a distinct leukocyte subset for the overall cytokine balance after treatment with BZ (blue), K777 (red), PYR (green), and FUR (pink) lead compounds. Groups were categorized as noninfected subjects (NI, n = 18) and Chagas disease patients (CD, n = 20).

FIG 6

Functional biomarkers upregulated by anti-T.…

FIG 6

Functional biomarkers upregulated by anti-T. cruzi lead compounds shown in Venn diagrams. Venn…

FIG 6

Functional biomarkers upregulated by anti-T. cruzi lead compounds shown in Venn diagrams. Venn diagrams were built for noninfected subjects and Chagas disease patients after treatment with BZ (blue), K777 (red), PYR (green), and FUR (pink) lead compounds in order to determine the induction levels of common biomarkers. The internal values in the diagram represent the number of single or common biomarkers among the lead compounds.

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