Systems Biology Reveals Relevant Gaps in Fc-γR Expression, Impaired Regulatory Cytokine Microenvironment Interfaced With Anti-Trypanosoma cruzi IgG Reactivity in Cardiac Chagas Disease Patients.

Juliana De A S Gomes,Isabela N P C Do Vale,Olindo A Martins-Filho,Andréa Teixeira-Carvalho,Renato Sathler-Avelar,João C P Dias,Silvana M Elói-Santos,Paula S Lage,Ana P B Wendling,Fernanda F De Araújo,Daniele M Vitelli-Avelar

doi:10.3389/fmicb.2018.01608

Juliana De A S Gomes, Isabela N P C Do Vale + Show 9 more

Open Access

https://doi.org/10.3389/fmicb.2018.01608

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Abstract

The systems biology approach has become an innovative tool when it comes to shedding light on the complex immune response underlying the development/maintenance of distinct clinical forms of Chagas disease. The goal of this study was to describe an integrative overview of Fc-γR expression, cytokine microenvironment and anti-Trypanosoma cruzi IgG interface in indeterminate-(IND) and cardiac-(CARD) patients. Data demonstrated that IND displayed an overall higher Fcγ-R expression (CD16; CD32; CD64) on neutrophils-(NEU), along with (CD16; CD64) on monocytes-(MON) as compared to CARD. Additionally, CARD presented an increased expression of CD32 in B-cells. While preserved frequency of IL-10-producing cells was observed in IND, decreased levels of IL-10+ phagocytes and enhanced TNF+ MON and NK-cells were observed in CARD. T. cruzi-antigen recall in vitro induces a general decrease of Fc-γR expression in Chagas disease patients, especially in CARD. Moreover, T. cruzi-antigen stimuli triggered a concomitant increase of IFN-γ+NEU/TNF+NK-cells and IL-10+MON/IL-10+B-cells in IND. Biomarker signatures further emphasized the contrasting Fc-γR expression and cytokine microenvironment observed in Chagas disease patients with distinct clinical forms. Up-regulation of Fc-γR expression (CD16 on NEU;MON;NK) was observed in IND, whereas a general decrease was reported for CARD. Moreover, while a mixed cytokine microenvironment (TNF; IL-10) was observed in IND, CARD presented a contrasting profile with up-regulation of TNF+NEU and IL-12+NEU. Integrative network analysis revealed a distinct assemblage of biomarkers, with CARD presenting a large number of negative internode connectivity in comparison with IND. The relevant gaps in Fc-γR expression and impaired regulatory cytokine microenvironment interfaced with the anti-T. cruzi IgG reactivity throughout an exacerbated negative connectivity may account for the development/maintenance of the clinical status of cardiac Chagas disease.

Highlights

MATERIALS AND METHODSChagas disease, caused by Trypanosoma cruzi, remains a serious public health problem and affects about 10 million people in Latin America (World Health Organization [WHO], 2017)
Data analysis demonstrated a general decrease of Fc-γR expression by innate immunity cells (NEU, MON, and NK-cells) in Chagas disease patients with the major effect observed in CARD, except for CD16 expression by MON, which was up regulated in IND (Figure 1B)
We have employed systems biology strategies to investigate the relationship between Fc-γR expression by distinct cell subsets and the cytokine microenvironment interfaced with anti-T. cruzi IgG reactivity to provide novel insights into the development/maintenance of distinct clinical status of cardiac Chagas disease

Summary

Introduction

MATERIALS AND METHODSChagas disease, caused by Trypanosoma cruzi, remains a serious public health problem and affects about 10 million people in Latin America (World Health Organization [WHO], 2017). Distinct levels of anti-T. cruzi antibodies have been observed in patients with different clinical forms of Chagas disease (Cordeiro et al, 2001). The Fc-γR represent the major interface between humoral and cellular immune responses. These molecules have been involved in activating several functions including phagocytosis, degranulation, cytokines production, and antibodies-dependent cellular cytotoxicity (Ravetch and Kinet, 1991). The down-regulation of Fc-γR expression by monocytes from IND was associated with a lower phagocytic capacity, but not with the anti-T. cruzi IgG observed in IND (Gomes et al, 2012). No previous report has addressed the integrative network assembled by distinct patterns of Fc-γR expression or the impact of soluble T. cruzi antigens on Fc-γR expression by circulating leucocytes subsets in patients with distinct clinical forms of Chagas disease

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