Phenotypic Features of Circulating Leukocytes from Non-human Primates Naturally Infected with Trypanosoma cruzi Resemble the Major Immunological Findings Observed in Human Chagas Disease

Abstract

BackgroundCynomolgus macaques (Macaca fascicularis) represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH) presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations.Methods and FindingsOur data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI). Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications.ConclusionsAltogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease.

Trypanosoma cruzi Infection in Non-Human Primates

“…Recent studies, including ours, have shown that their immunological response resembles what is observed in human Chagas disease, as briefly schemed in Figure 3 [1,6,18,21]. Our group has recently published a research on T. cruzi naturally infected cynomolgus macaques which displayed, in the peripheral blood, a similar immunological profile to that observed in humans, with high activity of cytotoxic cells and expansion of macrophages and activated T-cell subsets [21]. The infected animals exhibit higher frequency of NK Granzyme A + cells.…”

“…Studies focusing on aspects related to the synergic effect of the immune response and chemotherapeutic agents in humans and NPH are still scarce. Sathler-Avelar and colleagues [21,22,24] have provided insights about the relevance of a balanced immune response elicited after chemotherapeutic intervention to mediated parasite killing but minimize tissue damage. There are evidences supporting that a pro-inflammatory response mediated by IFN-γ acts synergistically with the drug treatment to accomplish effective trypanocidal events [24,41] and that simultaneous regulatory mechanisms elicited by IL-10 are relevant to control deleterious effects of therapeutic intervention [21,22,24].…”

Cynomolgus macaques naturally infected with Trypanosoma cruzi-I exhibit an overall mixed pro-inflammatory/modulated cytokine signature characteristic of human Chagas disease

“…In fact, we have recently demonstrated that cynomolgus macaques naturally infected with T . cruzi present a range of ex vivo phenotypic features of circulating leukocytes that are highly similar to those observed in human Chagas disease patients [ 14 ]. We also have demonstrated that infected cynomolgus macaques with no macroscopic evidence of cardiac/digestive commitment have elevated levels of circulating monocyte-subsets, cytotoxic NK-cells and activated CD8 + T-lymphocytes, as is observed in human Chagas disease [ 14 , 15 ].…”

Meta-Analysis of Aedes aegypti Expression Datasets: Comparing Virus Infection and Blood-Fed Transcriptomes to Identify Markers of Virus Presence

“…Decision trees were employed to identify a minimal set of gene expression measurements allowing separation between the infected from uninfected groups. This method analyzes all the phenotypic attributes (gene expression measurements) and selects the most relevant attributes that allow group classification (Sathler-Avelar et al, 2016 ). As input for tree construction, we used the 110 genes (and their expression values) that we identified as most related to infection independent of feeding background (available in Table S1 in Supplementary Material).…”